Erfolgreich durch internationale Zusammenarbeit

Oncology

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.22

Received 26 May 2026;
Accepted 20 July 2026;
Published 2 August 2026

CANNABINOIDS AND THE ENDOCANNABINOID SYSTEM IN ONCOLOGY: FROM SUPPORTIVE CARE TO EMERGING ANTICANCER STRATEGIES

Magdalena Korba¹ , Aleksandra Piętak² ,
Izabela Staszczyk³ , Roksana Hashemi⁴

¹ St. Anne’s Hospital, Miechow, Poland
² Jagiellonian University Medical College, Krakow, Poland
³ J. Gromkowski Provincial Specialist Hospital, Wroclaw, Poland
⁴ Provincial Specialist Hospital, Wroclaw, Poland

download article (pdf)

  abrokmagdalena@gmail.com

ABSTRACT

Background

The endocannabinoid system (ECS) regulates key physiological processes involved in pain, appetite, mood, immune function, and tumor biology, supporting growing interest in cannabinoids in supportive oncology and experimental anticancer research.

Aim

This narrative review critically evaluates current clinical, preclinical, and translational evidence on cannabinoids and the ECS in oncology, with a clear distinction between clinically supported applications in supportive cancer care and experimental data on possible anticancer mechanisms.

Materials and Methods

A structured literature search was conducted up to May 24, 2026, using PubMed as the primary database and Google Scholar as a supplementary source. Out of 721 identified records, 183 peer-reviewed publications were included in the narrative synthesis.

Results

Current clinical evidence most strongly supports the use of cannabinoid-based therapies for chemotherapy-induced nausea and vomiting. Evidence for cancer-related pain, appetite stimulation, sleep disturbances, fatigue, anxiety, and depression remains limited, heterogeneous, and patient-dependent. Preclinical studies indicate that cannabinoid signaling may influence tumor-related processes, including apoptosis, autophagy, angiogenesis, invasion, tumor microenvironment modulation, and immune regulation; however, robust clinical evidence demonstrating anticancer efficacy in humans is lacking. Cannabinoid-based therapies are also associated with dose-dependent adverse effects and clinically relevant CYP450-mediated drug-drug interactions, particularly in oncology patients receiving polypharmacy.

Conclusions

Cannabinoids currently have their most clearly supported role in supportive oncology, especially in the management of chemotherapy-induced nausea and vomiting. Their possible anticancer effects remain predominantly preclinical and do not support the use of cannabinoids as standard anticancer therapy in humans. Clinical use requires careful consideration of safety risks, drug-drug interactions, and individual patient characteristics.

Keywords: cannabinoids; endocannabinoid system; supportive oncology; cancer pain; cannabidiol; tetrahydrocannabinol; tumor microenvironment

INTRODUCTION

Phytocannabinoids are plant-derived cannabinoids primarily obtained from Cannabis species, which have attracted considerable scientific and clinical interest, particularly in pain management and supportive cancer care. Among them, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phytocannabinoids associated with a wide range of pharmacological effects, including analgesic, antiemetic, anxiolytic, and potential antitumor activities, although the latter have been demonstrated predominantly in preclinical studies, including in vitro experiments and animal models [1]. Cannabinoids have gained increasing attention in recent years as potential agents in supportive oncology, reflecting a broader interest in the physiological role of the endocannabinoid system (ECS) in human health and disease. The ECS, a complex cell-signaling network comprising endogenous ligands, receptors, and metabolic enzymes, is widely expressed throughout the central nervous system and peripheral tissues, including components of the immune system [2,3]. To date, two major cannabinoid receptors, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), have been identified and characterized in mammalian tissues. Cannabinoid effects in the central and peripheral nervous systems are primarily mediated by CB1R, which is predominantly expressed on neurons, whereas CB2R is mainly found in immune cells but can also be expressed in other cell types, including cancer cells [4–6]. In oncology, cannabinoids are primarily investigated for their role in supportive care, particularly in alleviating cancer- and treatment-related symptoms, whereas their potential anticancer effects remain experimental and are supported mainly by preclinical evidence. The involvement of the ECS in the regulation of pain, appetite, mood, and immune function has prompted growing interest in its relevance to cancer care, particularly in the management of treatment-related symptoms [7–9]. At the same time, accumulating preclinical evidence suggests that modulation of the ECS may influence tumor-related processes, further expanding the scope of research into cannabinoids in oncology [10,11]. These observations have stimulated an increasing number of clinical and translational studies exploring the role of cannabinoids in cancer patients [7,12]. However, despite encouraging preclinical findings, clinical evidence supporting the efficacy and safety of cannabinoids in oncology remains limited and heterogeneous.

Aim

The aim of this narrative review is to critically evaluate current clinical, preclinical, and translational evidence on the role of cannabinoids and the endocannabinoid system in oncology, with a clear distinction between clinically supported applications in supportive cancer care and experimental data on possible anticancer mechanisms.

Objectives

• To assess clinical evidence on the use of cannabinoids in supportive oncology, including chemotherapy-induced nausea and vomiting, cancer-related pain, appetite loss, sleep disturbances, fatigue, anxiety, and depression.
• To analyze the mechanisms through which cannabinoids and the endocannabinoid system may influence cancer-related symptom control and tumor-related processes, including pain signaling, appetite and sleep regulation, apoptosis, oxidative stress, angiogenesis, tumor invasion, the tumor microenvironment, and immune regulation.
• To distinguish experimental preclinical findings on possible anticancer effects from clinically proven anticancer efficacy in humans.
• To evaluate key safety issues relevant to oncology patients, including dose-dependent adverse effects, neuropsychiatric, cardiovascular, and hepatic risks, and CYP450-mediated drug-drug interactions.

MATERIALS AND METHODS

This study was conducted as a narrative literature review to evaluate the current evidence regarding cannabinoids and the ECS in oncology, with particular emphasis on supportive cancer care, cancer-related pain, potential anticancer mechanisms, immunomodulatory effects, and the safety and tolerability of cannabinoid-based therapies.

A structured literature search was conducted primarily using PubMed as the main biomedical database. Google Scholar was used only as a supplementary search tool to identify additional relevant publications and to screen citation-linked articles when appropriate. The final literature search was completed on May 24, 2026.

The PubMed search was performed using combinations of keywords related to two principal topics: (i) the supportive use of cannabinoids in oncology and (ii) the potential anticancer effects of cannabinoids. Representative search phrases included endocannabinoid system and oncology, cannabinoids and chemotherapy-induced nausea and vomiting, cannabinoids and cancer pain, cannabinoids and cachexia, cannabinoids and sleep disturbances, cannabinoids and cancer-related fatigue, cannabinoids and anxiety in cancer, cannabinoids and depression in cancer, cannabinoids and glioma, cannabinoids and tumor microenvironment, cannabinoids and immunotherapy, and cannabinoids and anticancer mechanisms. Search terms were adapted as appropriate throughout the literature search.

The PubMed search identified 721 records. After removal of duplicate records, titles and abstracts were screened for relevance to the objectives of this review. Of the identified records, 538 were excluded during title, abstract, and full-text screening because they did not meet the predefined eligibility criteria, leaving 183 publications for inclusion in the narrative synthesis.

Priority was given to randomized controlled trials, systematic reviews, meta-analyses, observational studies, translational research, and preclinical experimental studies published in peer-reviewed journals. Seminal publications published between 1975 and 2010 were included where necessary to provide historical context and to describe ECS physiology, cannabinoid receptor biology, and fundamental molecular mechanisms. The primary analysis focused on literature published between 2015 and 2026 to reflect recent developments in cannabinoid-based oncology research.

Eligible studies included publications investigating the role of cannabinoids in supportive oncology, including chemotherapy-induced nausea and vomiting, appetite loss and cancer-related cachexia, sleep disturbances, fatigue, cancer-related pain, anxiety, and depression, as well as studies evaluating potential anticancer mechanisms, tumor biology, the tumor microenvironment, immune modulation, and interactions between the ECS and cancer immunotherapy. Mechanistic and translational studies outside oncology were also included when considered essential for understanding ECS physiology, cannabinoid pharmacology, and symptom modulation.

Publications not available in English, duplicate records, and studies not directly relevant to the objectives of this review were excluded.

RESULTS

The selected literature demonstrated that cannabinoids may provide clinically relevant benefits primarily in supportive oncology, particularly in the management of chemotherapy-induced nausea and vomiting, appetite loss, sleep disturbances, and selected pain syndromes. Evidence supporting efficacy in cancer-related pain, especially neuropathic and opioid-refractory pain, remained limited and heterogeneous, with inconsistent findings across randomized controlled trials. Preclinical studies consistently demonstrated that cannabinoid signaling may influence multiple tumor-related processes, including proliferation, apoptosis, angiogenesis, invasion, oxidative stress, and immune regulation across various cancer models. However, robust clinical evidence confirming antitumor efficacy in humans was lacking. The reviewed studies additionally highlighted important safety considerations, including dose-dependent adverse effects and clinically relevant pharmacokinetic drug–drug interactions. Overall, the available evidence suggests that cannabinoids currently hold greater relevance in supportive cancer care than as established anticancer therapies.

Cannabinoids in the Management of Chemotherapy-Induced Side Effects

Chemotherapy, despite its effectiveness in cancer treatment, is associated with numerous adverse effects that can significantly impair patients’ quality of life. Among the most frequently reported complications are nausea and vomiting, loss of appetite, sleep disturbances, and cancer-related fatigue. These symptoms represent a substantial therapeutic challenge, may negatively affect treatment adherence, and often require comprehensive supportive care interventions [13–16].

Effect of Cannabinoids on Chemotherapy-Induced Nausea and Vomiting

Evidence from preclinical studies, including animal models, suggests that cannabinoids exert antiemetic effects primarily through activation of CB1R in brainstem regions involved in emetic regulation [17,18]. CB1 receptors are highly expressed within the dorsal vagal complex (DVC), particularly in the dorsal motor nucleus of the vagus (DMNX) and the nucleus tractus solitarius (NTS), which are considered major sites of THC action [18]. Activation of CB1R leads to presynaptic inhibition of neurotransmitter release involved in emetic signaling, particularly glutamate, and may additionally modulate neuropeptidergic pathways, including substance P-mediated transmission [19,20]. Cannabinoids also influence serotonergic (5-hydroxytryptamine, 5-HT) and dopaminergic signaling systems implicated in the initiation and propagation of nausea and vomiting [21].

Functionally, these effects result in suppression of emetogenic signal integration within the DVC, attenuation of visceral afferent transmission in the NTS, reduced chemosensory activity of the area postrema, and modulation of medullary neuronal networks coordinating the emetic reflex [17,18,22]. Collectively, these mechanisms contribute to the inhibition of both sensory and motor components of vomiting, providing a neurobiological basis for the antiemetic properties of cannabinoids.

In addition to their central effects, cannabinoids modulate gastrointestinal signaling by reducing gastric motility and decreasing the excitability of vagal afferent pathways, thereby limiting the transmission of visceral signals to brainstem emetic circuits [23–25]. These actions are primarily mediated through CB1 receptor activation within the enteric nervous system, particularly on neurons of the myenteric plexus. CB1 receptor activation inhibits the release of excitatory neurotransmitters, especially acetylcholine, leading to reduced enteric neuronal excitability and impaired coordinated peristalsis. At the systemic level, these effects contribute to delayed gastric emptying and slowed intestinal transit, reflecting the inhibitory role of the endocannabinoid system in gastrointestinal motor regulation [25].

Dronabinol (synthetic Δ9-THC) and synthetic cannabinoids such as nabilone have been evaluated in patients undergoing chemotherapy. Randomized controlled trials conducted between the 1970s and 1990s demonstrated that these agents significantly reduce chemotherapy-induced nausea and vomiting compared with placebo and, in some studies, exhibit comparable or superior efficacy to conventional antiemetic therapies available at the time, particularly in patients receiving highly emetogenic regimens such as cisplatin-based chemotherapy [26–31].

However, despite demonstrated antiemetic efficacy in clinical settings, the precise central mechanisms underlying these effects in humans have not been directly confirmed and remain largely inferred from preclinical animal studies and neuroanatomical evidence.

Effects of Cannabinoids on Appetite and Cancer-Related Cachexia

Cannabinoids, particularly THC, may stimulate appetite in patients undergoing chemotherapy through activation of CB1R within the central nervous system, especially in hypothalamic regions involved in appetite regulation [32]. CB1 receptor activation reduces satiety signaling while enhancing hunger perception and food-related reward processing through modulation of dopaminergic pathways [33,34]. Clinical studies have demonstrated that dronabinol may improve appetite in patients with cancer-related cachexia. In patients with advanced cancer, cannabinoid treatment has been associated with subjective improvements in appetite. However, in comparative studies, dronabinol was generally less effective than megestrol acetate, and its effects on body weight remained modest and inconsistent [35,36].

Effects of Cannabinoids on Sleep Quality and Sleep Disturbances

CB1 receptors are expressed in several brain regions involved in sleep regulation, including the hypothalamus, brainstem, basal forebrain, and limbic system [37]. Sleep disturbances are highly prevalent among patients undergoing chemotherapy and constitute an important component of the overall cancer-related symptom burden, significantly impairing quality of life [38].

The endocannabinoid system contributes to sleep regulation and circadian homeostasis through modulation of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission within central sleep-wake regulatory pathways. Experimental studies suggest that cannabinoids may influence both sleep initiation and sleep architecture. In a randomized, double-blind, placebo-controlled crossover trial conducted in healthy volunteers, THC reduced sleep latency and increased subjective sleepiness, particularly at higher doses [39]. The same study also demonstrated dose-dependent alterations in sleep architecture, affecting both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep [39]. Additional randomized electroencephalography (EEG)-based human studies have reported cannabinoid-associated changes in sleep-stage distribution, including reductions in REM sleep and alterations in cortical oscillatory activity consistent with modified sleep architecture [40].

These effects appear to be dose-dependent and may diminish with chronic exposure due to the development of tolerance [41,42]. Although clinical evidence in oncology patients remains limited, the sleep-modulating properties of cannabinoids may have potential relevance in supportive cancer care, as improvements in sleep continuity and reductions in nocturnal awakenings could indirectly contribute to better perceived restfulness and reduced fatigue severity [43,44].

Potential Effects of Cannabinoids on Cancer-Related Fatigue

Cancer-related fatigue (CRF), including persistent fatigue following chemotherapy, is among the most common and distressing symptoms experienced by oncology patients. It is a multifactorial condition that cannot be fully explained by activity level or insufficient rest and is thought to arise from a combination of inflammatory processes, neuroendocrine dysregulation, sleep disturbances, anemia, psychological factors, and cancer- or treatment-related metabolic alterations such as cachexia [45]. CRF frequently persists long after completion of chemotherapy and substantially impairs quality of life.

Cannabinoids have no established direct effect on the underlying biological mechanisms of cancer-related fatigue; however, they may contribute indirectly to symptom relief. Activation of CB1 receptors within the central nervous system by THC may improve sleep quality, reduce chemotherapy-induced nausea and pain, and enhance appetite and mood through modulation of dopaminergic reward pathways. Collectively, these effects may alleviate symptoms that contribute to fatigue, including poor sleep, inadequate caloric intake, and psychological distress [46]. Clinical evidence from randomized trials has not consistently demonstrated a direct reduction in fatigue severity. Nevertheless, some patients report improvements in overall well-being and symptom burden during cannabinoid treatment, which may indirectly translate into a perceived reduction in fatigue intensity [47,48].

Cannabinoids as Adjuncts in Chronic Pain

Cancer-related pain is a complex and multifactorial condition affecting a substantial proportion of patients across all stages of malignancy. Its etiology includes direct tumor invasion, treatment-related complications associated with chemotherapy, radiotherapy, and surgery, as well as comorbid conditions, often resulting in mixed nociceptive and neuropathic pain components [49,50]. Despite advances in oncological care and the widespread use of opioid and adjuvant analgesic therapies, a significant proportion of patients continue to experience inadequate symptom control [51,52]. Opioid analgesics remain the cornerstone of pharmacological management for cancer-related pain, particularly in patients with moderate to severe symptoms, and are consistently recommended as first-line therapy because of their well-established efficacy in both nociceptive and neuropathic pain states [53]. However, despite their clinical effectiveness, opioid therapy is frequently associated with dose-limiting adverse effects and requires careful titration and monitoring [54,55]. Evidence from systematic reviews and meta-analyses continues to support the central role of opioids in cancer pain management while simultaneously highlighting the need for adjunctive therapeutic strategies aimed at optimizing analgesia and reducing treatment-related toxicity [56]. Poorly controlled cancer pain is strongly associated with impaired physical and psychological functioning, diminished quality of life, and increased healthcare burden [57,58]. Consequently, growing attention has been directed toward adjunctive multimodal approaches, including cannabinoids, as potential supportive options in the management of cancer-related pain.

Endocannabinoid Mechanisms of Pain Modulation

The endocannabinoid system modulates pain through complementary but functionally distinct mechanisms mediated by CB1 and CB2 receptors. CB1 receptors are predominantly expressed within the central nervous system, where their activation inhibits presynaptic neurotransmitter release, whereas CB2 receptors are primarily localized on peripheral immune cells and contribute to the attenuation of proinflammatory cytokine production [59].

CB1 receptor activation suppresses nociceptive signal transmission within key spinal and supraspinal pain-processing regions, leading to attenuation of pain perception and modulation of both sensory and affective dimensions of pain [60,61]. These effects are supported by preclinical evidence demonstrating CB1-mediated antinociception across multiple experimental pain models [62–65]. In parallel, activation of CB2 receptors reduces peripheral sensitization and attenuates inflammatory components of chronic pain [66,67], with preclinical syntheses reporting reductions in both inflammatory and neuropathic pain-related behaviors [67,68].

THC acts as a partial agonist at both CB1 and CB2 receptors, producing analgesic effects primarily through central inhibition of nociceptive processing and peripheral immunomodulatory activity [69,70]. However, its clinical application is limited by dose-dependent psychoactive adverse effects [71,72].

In contrast, CBD exhibits low affinity for CB1 and CB2 receptors and influences pain signaling predominantly through indirect mechanisms. CBD may enhance endocannabinoid tone by inhibiting anandamide degradation, thereby potentiating endogenous analgesic signaling [73]. It also interacts with transient receptor potential (TRP) channels, contributing to desensitization of nociceptive pathways and reduced pain transmission [74]. In addition, CBD exerts anti-inflammatory effects through modulation of cytokine production and immune cell activity [74–76]. Importantly, CBD may attenuate some of the psychoactive and anxiogenic effects associated with THC, potentially improving the tolerability of cannabinoid-based therapies [77,78].

Collectively, THC and CBD may provide complementary analgesic mechanisms by combining central antinociceptive effects with peripheral anti-inflammatory and neuromodulatory actions, while potentially improving the overall safety and tolerability profile of cannabinoid-based interventions [79–81].

The supportive oncology effects of cannabinoids discussed in this section are summarized in Table 1. The table provides an overview of the principal chemotherapy-related symptoms addressed in this review, including chemotherapy-induced nausea and vomiting, appetite loss and cancer-related cachexia, sleep disturbances, cancer-related fatigue, and cancer-related pain. For each symptom, it summarizes the proposed role of cannabinoids, the main reported clinical effects, and the overall strength of the available evidence. Overall, the strongest clinical evidence supports the use of cannabinoids for chemotherapy-induced nausea and vomiting. In contrast, evidence for appetite stimulation, sleep disturbances, cancer-related fatigue, and cancer-related pain remains limited and heterogeneous, with reported benefits varying across patient populations and clinical studies.

Evidence for Cannabinoids in Neuropathic Cancer Pain: A Cautious Perspective

Neuropathic cancer pain is a distinct subtype of cancer-related pain resulting from injury or dysfunction of the somatosensory nervous system caused either by tumour involvement or cancer therapies [50,82–84]. Its pathophysiology involves both peripheral and central mechanisms, including ectopic neuronal activity following nerve injury and central sensitization associated with impaired inhibitory control, ultimately leading to persistent amplification of pain signaling [85,86]. Common oncological causes include tumour-related plexopathies and radiculopathies, chemotherapy-induced peripheral neuropathy, and radiation-induced nerve injury associated with fibrosis and demyelination [87,50].

Neuropathic cancer pain is frequently incompletely responsive to opioid therapy alone, reflecting its distinct neurobiological mechanisms. Consequently, optimal management typically requires a multimodal approach combining opioids with adjuvant agents such as gabapentinoids, serotonin-noradrenaline reuptake inhibitors, or tricyclic antidepressants, together with interventional techniques or palliative radiotherapy in selected patients [88–90].

Cannabinoids have been investigated as potential adjuvant analgesics in neuropathic cancer pain because of their ability to modulate endocannabinoid signaling pathways involved in nociceptive processing and neuroinflammation. However, despite a strong mechanistic rationale, randomized controlled trials evaluating their efficacy in this setting remain limited and are frequently characterized by small sample sizes, resulting in insufficient statistical power and limited generalizability. Available findings are inconsistent, with clinically meaningful analgesic responses observed only in subsets of patients rather than across entire study populations [91–94].

Furthermore, a substantial proportion of the current evidence is derived from studies conducted in non-oncological neuropathic pain populations or from meta-analyses pooling heterogeneous patient groups, which limits direct extrapolation to cancer patients. Nevertheless, the observed indications of potential benefit, together with evidence from other neuropathic pain conditions, suggest that cannabinoids may represent a possible adjunctive therapeutic option warranting further investigation in adequately powered, high-quality clinical studies [91–94].

THC-containing preparations, particularly THC/CBD combinations, appear to provide greater symptomatic benefit than cannabidiol-dominant formulations in neuropathic pain. However, the overall magnitude of effect remains modest and clinically variable, and robust randomized evidence demonstrating comparable efficacy in neuropathic cancer pain is currently lacking [7,80].

Accordingly, current expert consensus statements and clinical guidelines do not recommend cannabinoids as first-line therapy and instead reserve their use for carefully selected patients with refractory symptoms within a multimodal pain-management strategy [80,95].

Therapeutic Potential of Cannabinoids in Opioid-Refractory Cancer Pain

Cannabinoid-based medicinal preparations are currently available in clinical practice. Among them, nabiximols is a plant-derived formulation containing a standardized combination of THC and CBD, most commonly administered as an oromucosal spray under the trade name Sativex [96].

Nabiximols has been investigated as an adjunctive therapy for patients with advanced cancer pain inadequately controlled by opioid treatment. Although several therapeutic strategies exist for refractory cancer pain, the addition of adjuvant analgesics remains one of the most practical and clinically acceptable approaches [97].

In a randomized controlled trial involving patients with advanced cancer and opioid-refractory pain, adjunctive treatment with a THC/CBD combination failed to achieve statistical significance for the primary efficacy endpoint. Nevertheless, a higher proportion of responders was observed in the cannabinoid group compared with placebo, suggesting a possible analgesic effect in a subset of patients. Interestingly, this response appeared more pronounced at lower to moderate doses, indicating a potential non-linear or dose-dependent relationship. However, because the primary endpoint was not met, these findings should be considered exploratory rather than confirmatory [97].

Similar findings were reported in another randomized controlled trial evaluating cannabinoid treatment in patients with advanced cancer and persistent pain despite optimized opioid therapy. Although the intention-to-treat (ITT) analysis did not demonstrate a statistically significant benefit for the primary endpoint, improvements were observed in the per-protocol population and in selected secondary outcomes, including patient-reported symptom burden and quality of life. The discrepancy between analytical approaches, however, limits the robustness and generalizability of these findings [98].

Evidence from systematic reviews remains similarly cautious. A Cochrane review including four randomized controlled trials and more than 1300 patients with opioid-refractory cancer pain found no clinically meaningful difference between cannabis-based medicines and placebo with respect to mean pain intensity reduction or achievement of ≥30% pain relief. In addition, cannabinoid-based treatments were associated with a higher incidence of adverse events [99].

Overall, current evidence evaluating nabiximols as adjunctive therapy for opioid-refractory cancer pain remains inconsistent. Although some studies suggest possible benefits in selected patients and improvements in secondary outcomes, primary efficacy endpoints are generally not achieved, and the overall evidence base remains insufficient to demonstrate a clinically meaningful benefit at the population level [97–99].

Cannabinoids in depression and anxiety treatment in cancer patients

Receiving cancer diagnosis can be a life-altering experience that may lead to mental health disorders, even among individuals with no prior psychiatric history [100]. Anxiety and depression are among the most commonly reported mental disorders and frequently coexist [101]. The ECS has been linked to the pathophysiology of major depressive disorder through CB1 and CB2 receptor polymorphisms, modulation of hypothalamic-pituitary-adrenal (HPA) axis signaling, regulation of inflammatory processes and neurogenesis stimulation [102]. Consequently, cannabinoids have been proposed as potential agents for managing symptoms of anxiety and depression, which could hypothetically improve psychological outcomes in patients with cancer. Some studies have reported improvements in self-reported anxiety and depression scores among patients receiving cannabis-based products; however the effects appeared to vary depending on cannabis dose, the THC-to-CBD ratio, and the route of administration [103]. Conversely, other studies suggest that current cannabis use may constitute an independent risk factor for depression in specific subgroups, including female cancer patients, individuals who initiated cannabis use after the age of 17 years, and cancer patients without a history of cocaine use [104]. The potential anxiolytic effect of CBD was also evaluated in a randomized controlled trial involving women with advanced breast cancer, in which a single oral dose of 400mg CBD resulted in lower anxiety levels compared with placebo; however, the difference did not reach statistical significance [105]. Finally, a metaanalysis investigating the use of medicinal cannabis for anxiety, depression and stress in patients with cancer concluded that the available evidence remains insufficient, emphasizing that none of the included studies assessed mental health as a primary outcome or therapeutic target [106]. Therefore, well-designed clinical trials are still needed to enable a clear assessment of the efficacy and safety of cannabinoids in this population.

Symptom Clusters in Oncology: Relevance for Cannabinoid Therapy

Symptom clusters refer to the co-occurrence of two or more interrelated symptoms that may share common underlying mechanisms and interact to exacerbate overall symptom burden, representing an important target for integrated therapeutic approaches in oncology. Frequently reported clusters include combinations such as pain, anxiety or depression, and sleep disturbances, which collectively contribute to significant impairment in quality of life [107–111]. These symptoms are often linked through overlapping biological pathways, including neuroinflammatory processes [112] and dysregulation of central nervous system signaling [113], as well as bidirectional psychological interactions [114,115]. Importantly, symptom clusters represent a relevant therapeutic target, as interventions addressing one component may influence the entire cluster [116]. Emerging evidence suggests that cannabinoids may exert multimodal effects across multiple symptom domains commonly included in cancer-related symptom clusters, particularly pain, anxiety, sleep disturbances, appetite loss, and chemotherapy-induced nausea and vomiting. A recent systematic review and meta-analysis reported potential benefits in cancer-related pain and anxiety, with additional but less consistent effects on insomnia, appetite, and chemotherapy-induced nausea and vomiting. However, these findings were characterised by substantial heterogeneity and very low certainty of evidence [117]. Overall, while cannabinoids may represent a mechanistically plausible option for multimodal symptom management in oncology, current clinical evidence remains insufficient to support their use as an established intervention for symptom clusters.

The Endocannabinoid System as a Potential Therapeutic Target in Oncology

Recent studies indicate that the ECS plays an important role in oncogenesis and tumor progression. Activation of cannabinoid receptors has been linked to suppression of cancer cell growth, promotion of apoptosis, and inhibition of angiogenesis. Overall, these effects point to the ECS as a potentially valuable target for future cancer therapies [10,118].

Anti-Tumor Mechanisms of Cannabinoid Signaling in Glioma Models

Among the malignancies investigated to date, glioma models have provided some of the most compelling evidence supporting the anti-tumor effects of cannabinoid signaling. Glioma studies have demonstrated that activation of cannabinoid receptors can suppress tumor growth through modulation of key signaling pathways [119]. Glioma cells express cannabinoid-sensitive G protein-coupled receptors (CB1R and CB2R), whose activation has been shown to modulate key cancer hallmarks, including proliferation, apoptosis resistance, angiogenesis, and invasiveness [120,121]. In high-grade gliomas, increased CB2R expression is mainly observed in vascular endothelial cells and infiltrating immune cells, although its presence has also been reported in tumor cells [122–126]. In contrast, findings regarding CB1R expression remain inconsistent across studies, although available evidence suggests that CB1R is predominantly localized in glioma cells [124,125,127].

In a pilot phase I clinical study involving patients with recurrent glioblastoma multiforme, intracranial administration of THC into the tumor resection cavity was evaluated for safety and potential antitumor activity. The treatment was generally well tolerated and was associated with decreased tumor cell proliferation, reflected by reduced Ki-67 immunoreactivity in post-treatment tumor samples. Additionally, THC administration was linked to the activation of apoptotic pathways in glioma cells. Collectively, these findings suggest that cannabinoids may exert direct antiproliferative and proapoptotic effects in glioblastoma, supporting further investigation of the endocannabinoid system as a potential therapeutic target in oncology [128].

ER Stress–Mediated Pro-Apoptotic Effects of Cannabinoid Signaling

Endocannabinoid signaling may induce glioma cell death through transient receptor potential vanilloid type 1 (TRPV1)-mediated endoplasmic reticulum (ER) stress. Fatty acid ethanolamides, including anandamide, released by neural progenitor cells activate TRPV1 channels localized on the endoplasmic reticulum of neighboring glioma cells, leading to Ca²⁺ release into the cytoplasm and depletion of ER calcium stores. This process triggers phosphorylation and inhibition of eukaryotic initiation factor 2 alpha (eIF2α), followed by activation of activating transcription factor 4 (ATF4) and activating transcription factor 3 (ATF3), ultimately promoting glioma cell death [129]. In parallel, activation of cannabinoid receptors CB1R and CB2R by THC and other agonists induces glioma cell apoptosis primarily through de novo synthesis of ceramide, a bioactive sphingolipid. Ceramide accumulation within the endoplasmic reticulum initiates ER stress signaling [130–132], leading to sequential activation of stress-related mediators including p8, ATF4, and C/EBP homologous protein (CHOP). Downstream of this cascade, ATF4/CHOP signaling promotes induction of tribbles pseudokinase 3 (TRIB3), which inhibits the serine/threonine kinase Akt (protein kinase B). This results in suppression of mechanistic target of rapamycin complex 1 (mTORC1) activity, activation of autophagy, and amplification of mitochondrial dysfunction, thereby reinforcing the pro-apoptotic response [133,134].

Increased oxidative stress

CB1R/CB2R activation in glioma cells has been consistently associated with the induction of oxidative stress, primarily through enhanced generation of reactive oxygen species (ROS) and mitochondrial dysfunction. This redox imbalance leads to damage to lipids, proteins, and DNA, thereby amplifying pro-apoptotic signaling and promoting glioma cell death. These effects are particularly evident in studies linking cannabinoid signaling to ER stress and oxidative stress-mediated cytotoxicity in glioma models [120,135].

Inhibition of the G1/S phase cell-cycle transition

Cannabinoid receptor activation exerts anti-proliferative effects by inducing cell-cycle arrest at the G1 phase, thereby preventing progression into DNA synthesis (S phase). This effect is mediated through downregulation of cyclins and cyclin-dependent kinase (CDK) activity, often accompanied by induction of cell-cycle inhibitors. Such regulation of cell-cycle checkpoints has been reported in studies linking cannabinoid signaling to suppression of proliferative pathways in tumor cells [121,136].

Modulation of transcriptional regulators

CB1R/CB2R signaling has been shown to modulate early-response transcription factors, including early growth response protein 1 (Egr1), which are involved in cellular stress responses, differentiation, and proliferation control. Altered Egr1 expression may contribute to downstream regulation of genes governing apoptosis and growth arrest, thereby reinforcing the anti-tumor effects of cannabinoid signaling. Early evidence of cannabinoid-induced modulation of immediate early genes, including Egr1, was reported in foundational studies [136,137] and later confirmed in glioma-specific models [120].

Reduced angiogenic potential and decreased invasive capacity of glioma cells

Activation of CB1R/CB2R has been shown to impair key processes required for glioma progression, including angiogenesis and cellular invasion. One of the central mechanisms underlying the anti-angiogenic effect is downregulation of pro-angiogenic factors, particularly vascular endothelial growth factor (VEGF), leading to reduced endothelial cell recruitment and impaired formation of functional tumor vasculature [138,139]. In parallel, cannabinoid signaling reduces the invasive capacity of glioma cells by modulating the expression and activity of proteins involved in extracellular matrix degradation, including matrix metalloproteinases (MMPs), as well as by affecting cytoskeletal dynamics and cell adhesion pathways. Collectively, these changes limit tumor cell migration through brain parenchyma and infiltration of surrounding tissue [140]. Overall, the inhibition of angiogenesis and invasion contributes to a less permissive tumor microenvironment, restricting both nutrient supply and local tumor spread, and represents a key component of cannabinoid receptor-mediated anti-tumor activity observed in in vivo glioma models [138–140].

Preclinical Studies of Cannabinoid Anticancer Effects in Various Tumor Types

Cannabinoids have demonstrated potential antitumor effects in preclinical studies across multiple cancer types, including gliomas, breast, lung, prostate, pancreatic, and colorectal cancers, melanoma, as well as certain leukemias and lymphomas. However, it should be emphasized that most of the available evidence derives from in vitro experiments and animal models, while robust clinical evidence confirming the efficacy of cannabinoids as anticancer therapies in humans remains lacking [141–143].

Breast Cancer Growth and Metastasis

In preclinical experimental studies combining in vitro and in vivo models, CBD has been shown to significantly downregulate the expression of inhibitor of DNA binding 1 (ID-1) in highly aggressive MDA-MB-231 breast cancer cells. This reduction in ID-1 levels is associated with decreased proliferation, invasiveness, and metastatic potential of cancer cells. In mouse xenograft models, CBD treatment results in a reduction in lung metastases, both in number and size, suggesting interference with key steps of the metastatic cascade, including tumor cell dissemination and colonization of distant organs [144]. Mechanistically, CBD-induced effects have been linked to increased oxidative stress, characterized by elevated ROS levels and activation of extracellular signal-regulated kinase (ERK) signaling. These changes contribute to the regulation of genes involved in the aggressive cancer phenotype, including secondary suppression of ID-1 expression, ultimately leading to reduced migratory and invasive capacity of breast cancer cells in experimental models [144]. Importantly, the CBD-ID-1-invasiveness axis has been well characterized in cell culture and animal studies but has not yet been validated in clinical settings. Therefore, although preclinical data are promising, they do not currently support CBD as an established therapeutic option for breast cancer in humans.

Modulation of Tumor Progression in Lung Cancer Models

In preclinical models of non-small cell lung cancer (NSCLC) and other lung cancer cell lines, CBD has been shown to modulate key processes involved in tumor progression and metastasis. Experimental studies indicate that CBD reduces cancer cell migration and invasive capacity, including through modulation of extracellular matrix interactions. These effects are associated with alterations in epithelial-mesenchymal transition (EMT)-related pathways, which are critical for metastatic dissemination. In addition, preclinical models suggest that CBD may impair angiogenic signaling and reduce stem-like properties (“stemness”) of cancer cells, contributing to a less aggressive tumor phenotype [145]. Beyond effects on metastatic traits, CBD has been reported to induce cancer cell death through apoptosis and autophagy-dependent mechanisms. It may also enhance cellular stress responses, including DNA damage signaling and modulation of tumor suppressor pathways such as p53, thereby contributing to growth inhibition in lung cancer models. Furthermore, emerging evidence suggests that CBD can modulate the tumor microenvironment by affecting stromal components such as fibroblasts and by regulating inflammatory signaling, which together may influence tumor progression dynamics [146,147]. Despite these findings, there is currently a lack of robust clinical evidence demonstrating that CBD inhibits metastasis or improves outcomes in lung cancer patients. Therefore, all observed effects remain strictly preclinical and based on in vitro and animal model data.

Preclinical Antitumor Effects of CBD and THC in Neuroblastoma Models

In a preclinical study combining in vitro experiments and in vivo mouse xenograft models of neuroblastoma, both CBD and THC demonstrated significant antitumor activity. The two compounds reduced tumor cell viability and impaired invasive properties in cultured neuroblastoma cells. In vivo, both cannabinoids inhibited tumor growth in xenograft-bearing mice. Notably, CBD consistently showed greater efficacy than THC across several experimental endpoints, including stronger reductions in cell viability and invasive capacity, suggesting a more potent overall antitumor effect in this model [148]. In mechanistic terms, these effects were linked to the induction of apoptosis via activation of the caspase cascade, including caspase-3, along with disruption of mitochondrial function and pro-survival signaling. In parallel, CBD reduced migratory and invasive capacity of neuroblastoma cells, suggesting additional effects on pathways regulating cell motility and cytoskeletal organization [149]. Importantly, all available data are preclinical, with no confirmed evidence of these effects in humans.

Preclinical Antileukemic Effects

Across leukemia models, cannabinoids have been shown to reduce malignant cell viability primarily through activation of apoptotic signaling pathways. A central mechanism involves CB2R-dependent induction of ROS, leading to oxidative stress and activation of intrinsic apoptosis cascades [150]. In acute myeloid leukemia (AML) models, CBD induces apoptosis in HL-60 human promyelocytic cells, associated with caspase-3 activation and disruption of redox homeostasis, resulting in reduced tumor cell survival [151]. Similarly, in T-cell acute lymphoblastic leukemia (T-ALL) models, THC promotes apoptosis through mitochondrial dysfunction, including loss of mitochondrial integrity and modulation of ERK and Bcl-2-associated death promoter (Bad) signaling [152]. In addition, preclinical T-ALL studies suggest that CBD and related cannabinoids may engage stress-response pathways linked to Notch1 signaling, thereby suppressing leukemic cell proliferation and enhancing programmed cell death [153]. Importantly, these findings are derived exclusively from preclinical models, including cell lines and experimental systems, with no validated clinical evidence supporting antileukemic efficacy in humans.

The ECS and Cancer Immunotherapy

The ECS represents an emerging immunomodulatory network implicated in the regulation of tumor-immune interactions within the tumor microenvironment (TME), with the capacity to influence both anti-tumor immune responses and immune tolerance [118]. Current experimental and translational evidence has characterized CB2-associated signaling pathways in the context of tumor immune regulation, highlighting their context-dependent immunological effects and potential relevance to mechanisms underlying cancer immunotherapy [154–157].

The Role of CB2 in TME Immunoregulation

The TME refers to the complex, dynamic network of non-malignant cells, extracellular matrix components, signaling molecules, and physical conditions that surround and interact with tumor cells, collectively shaping cancer development, progression, and therapeutic response [158,159]. Within the TME, infiltrating immune populations, including T lymphocytes, tumor-associated macrophages (TAMs), dendritic cells, and myeloid-derived suppressor cells (MDSCs), express CB2 and are capable of producing endogenous cannabinoids, thereby establishing a localized, functionally active „immune endocannabinoid system” that contributes to the regulation of intra-tumoral immune signaling and homeostasis [118]. CB2 expression in macrophage-lineage cells is dynamically regulated depending on their activation state, especially under inflammatory conditions, suggesting its involvement in switching macrophage phenotypes that are relevant for TAMs and overall immune tone within the TME [160]. In parallel, CB2 signaling has been shown to exert immunosuppressive effects in the TME by reducing the cytotoxic activity of CD8+ T cells and natural killer (NK) cells, thereby weakening anti-tumor immune responses; experimental in vivo models demonstrate that loss of CB2 signaling enhances effector immune cell function and strengthens anti-tumor immunity [154]. Beyond immune cells, CB2 also modulates stromal components of the tumor niche, including vascular and inflammatory cells, by inhibiting pro-inflammatory signaling pathways such as tumor necrosis factor alpha (TNF-α)-dependent responses and reducing vascular smooth muscle and endothelial cell activation, thereby contributing to remodeling of the TME [157]. Collectively, these findings suggest that CB2 signaling may act as a context-dependent immunoregulatory pathway integrating immune, stromal, and vascular signals. By dynamically modulating pro- and anti-inflammatory responses, CB2 may contribute to immune homeostasis, limiting excessive inflammation while shaping anti-tumor immune surveillance within the tumor microenvironment. However, these observations have not yet been translated into validated clinical outcomes in oncological patients, and therefore the role of CB2 in cancer immunomodulation should currently be interpreted as a putative, rather than clinically established, therapeutic target. Beyond its role in shaping the tumor microenvironment, CB2 signaling also directly modulates the function of immune effector cells, thereby exerting systemic immunoregulatory effects on anti-tumor immunity.

Immunosuppressive Roles of the ECS in Cancer

CB2 activation in T lymphocytes has been shown in primary experimental studies to suppress T-cell receptor (TCR)-mediated immune activation, resulting in reduced interleukin-2 (IL-2) production and impaired effector T-cell function. Consequently, a decrease in Th1-type immune responses, including interferon gamma (IFN-γ)-dependent cytotoxic activity, is observed, which is critical for effective anti-tumor immunity. These effects have been demonstrated mechanistically in vitro, indicating direct immunomodulation of T-cell signaling following cannabinoid receptor activation [155]. However, CB2 signaling has also been shown in preclinical studies to promote a shift in macrophage polarization from classically activated M1 macrophages toward alternatively activated M2 macrophages, thereby contributing to an immunosuppressive TME [160]. In addition, immunosuppressive remodeling of the TME is reinforced by the accumulation of regulatory immune cell populations. Experimental tumor models demonstrate that MDSCs suppress T-cell activation and promote regulatory T cell (Treg) expansion via interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) signaling [161]. Moreover, MDSCs and Tregs engage in a bidirectional regulatory loop that sustains immunosuppression and inhibits cytotoxic CD8+ T-cell responses in a TGF-β-dependent manner [161,162]. In vivo studies support the association between increased Treg infiltration and impaired anti-tumor immunity [163]. Collectively, these findings indicate that MDSC- and Treg-driven immunological reprogramming contributes to tumor immune evasion and establishment of an immunosuppressive microenvironment. However, these immunosuppressive effects are not uniform across tumor types or microenvironmental contexts.

Contextual Immunological Effects of the Endocannabinoid System in Cancer

Experimental studies have demonstrated substantial variability in CB1 and CB2 expression across different malignancies, with high CB2 expression observed in several glioma subtypes, while other tumor entities display low or heterogeneous receptor expression, suggesting that ECS-mediated signaling may exert distinct biological effects depending on tumor histopathology and differentiation status. Accordingly, the bidirectional effects of the ECS in cancer are thought to depend on multiple context-specific factors, including tumor type, cannabinoid receptor expression levels, cellular composition of the tumor microenvironment, local concentrations of endogenous and exogenous cannabinoids, and the inflammatory status of the tissue [126,164]. Similarly, alterations in endocannabinoid levels and ECS-associated enzymes have been shown to differ between low- and high-grade gliomas, indicating that ECS activity changes dynamically during tumor progression and may influence tumor behavior in a stage-dependent manner [125]. In contrast, clinical correlative studies in colorectal cancer demonstrated that increased CB2 expression was associated with tumor progression and poorer patient survival, suggesting that CB2 signaling may also promote tumor-supportive pathways under specific biological conditions [165]. Collectively, these findings indicate that ECS signaling cannot be interpreted as uniformly pro- or anti-tumorigenic; rather, its immunological and biological effects appear to be highly dependent on tumor context, receptor distribution, microenvironmental composition, and inflammatory signaling, which may explain why ECS activity has been associated with both immunostimulatory and immunosuppressive outcomes in cancer.

Implications of Endocannabinoid Signaling for Cancer Immunotherapy

The immunomodulatory properties of the ECS may have important implications for cancer immunotherapy, particularly in the context of immune checkpoint inhibitors. Experimental studies have demonstrated that CB2 activation can increase Treg activity and IL-10 production while suppressing effector T-cell responses, thereby promoting an immunosuppressive phenotype that may impair anti-tumor immune responses and potentially reduce responsiveness to immunotherapy [156]. Conversely, murine tumor models indicate that loss of CB2 signaling enhances CD8+ T-cell and NK cell cytotoxic activity and improves responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, supporting a potential inhibitory role of CB2 in anti-tumor immunity [154]. As described above, ECS signaling also modulates key immune and stromal components of the tumor microenvironment, including T-cell activation, macrophage polarization, and the accumulation of immunosuppressive cell populations such as Tregs and MDSCs, thereby shaping immune surveillance and tumor progression. In addition, ECS-mediated attenuation of chronic inflammatory signaling may contribute to remodeling of the TME toward a less aggressive inflammatory state [157]. Accordingly, ECS signaling is increasingly considered both a potential therapeutic target and a biological factor capable of influencing the efficacy of contemporary cancer immunotherapies. However, these conclusions are primarily based on preclinical evidence, and further translational and clinical studies are required to determine their relevance in human cancer immunotherapy.

The principal preclinical anticancer mechanisms of cannabinoids discussed in this review are summarized in Table 2. The table provides an overview of the major tumor models and research areas in which cannabinoid signaling has been investigated, including glioma, breast cancer, lung cancer, neuroblastoma, leukemia, the tumor microenvironment, and cancer immunotherapy. For each area, it summarizes the cannabinoid or ECS component involved, the proposed molecular mechanisms, the type of supporting evidence, and the current level of clinical evidence.

Overall, available data consistently indicate that cannabinoids may influence multiple hallmarks of cancer, including apoptosis, endoplasmic reticulum stress, autophagy, oxidative stress, cell-cycle regulation, angiogenesis, tumor invasion, and immune modulation. However, these findings are derived predominantly from in vitro studies and animal models. With the exception of limited early-phase clinical observations in glioblastoma, there is currently no robust clinical evidence demonstrating that cannabinoids improve oncological outcomes or can be recommended as anticancer therapy in humans. Consequently, the anticancer effects of cannabinoids should presently be regarded as experimental and hypothesis-generating rather than clinically established.

Safety and Tolerability of Cannabinoid-Based Therapies in Clinical Settings

The safety profile of cannabinoids is complex and depends on multiple factors, including dose, the THC:CBD ratio [166–170], patient age and neurological status, comorbidities [170–178], ongoing oncological treatments, and concomitant medications [171,172,179–185].

Dose Dependent Adverse Effects and Drug Interactions

Higher doses of THC, and to a lesser extent higher doses of CBD, are associated with an increased risk of adverse effects, including sedation, dizziness, cognitive impairment, psychiatric symptoms, and pharmacokinetic drug interactions [167,168]. The risk of clinically relevant cytochrome P450 (CYP450)-mediated drug interactions appears to increase particularly at doses exceeding 30 mg/day for THC and 300 mg/day for CBD [166]. High-THC formulations are more frequently associated with neuropsychiatric adverse effects, whereas CBD may partially attenuate the psychoactive effects of THC [78,169]. Accordingly, CBD-dominant preparations are generally associated with a more favorable tolerability profile [168]. A meta-analysis conducted in adults aged ≥50 years demonstrated higher rates of adverse events with THC-containing and THC:CBD formulations, while CBD alone showed substantially better tolerability [170]. Clinical studies further suggest that combined THC:CBD extracts may provide improved tolerability and greater therapeutic efficacy compared with THC administered alone [168].

Age and Comorbidity Related Safety Considerations of Cannabinoid Therapy

A systematic review and meta-analysis in adults aged ≥50 years reported an increased incidence of somnolence, dizziness, dry mouth, and treatment discontinuation due to adverse events associated with THC-containing preparations [170]. THC-containing preparations require particular caution in individuals with psychiatric disorders or increased vulnerability to psychosis, as experimental studies demonstrate acute psychotomimetic effects of THC [178], while epidemiological meta-analyses consistently show a dose-dependent increase in the risk of psychotic disorders and earlier disease onset in susceptible populations [176,177]. These findings further support the presence of dose–response relationships and gene–environment interactions, suggesting that cannabis exposure may lower the threshold for psychosis in genetically or clinically vulnerable individuals [176]. Cannabinoid-based therapies also require careful consideration in patients with cardiovascular and neurological disorders. Systematic reviews and meta-analyses indicate that cannabis and THC-containing preparations are associated with an increased risk of major adverse cardiovascular events, including myocardial infarction and stroke, as well as dose-dependent autonomic effects such as tachycardia and blood pressure alterations [173–175]. Clinical trial data further indicate that high-dose CBD may be associated with elevations in hepatic transaminases and clinically relevant drug–drug interactions mediated through CYP450 enzymes, supporting the need for hepatic monitoring during cannabinoid therapy [172,186]. In contrast, renal excretion of THC and CBD appears limited, and dose adjustment is generally not required in mild renal dysfunction. However, clinical evidence in advanced kidney disease remains scarce, while emerging observational data suggest possible adverse renal outcomes in patients with pre-existing chronic kidney disease, warranting careful monitoring in this population [171].

CYP450 Mediated Drug–Drug Interactions of Cannabinoids

Cannabinoids, particularly THC and CBD, can produce clinically relevant pharmacokinetic drug-drug interactions with a wide range of medications [172], including opioids [179], benzodiazepines [180], antidepressants [181], antiepileptics [182], certain anticancer agents [171] and immunotherapies [183]. These interactions are primarily mediated through modulation of the cytochrome P450 (CYP) enzyme system, particularly cytochrome P450 (CYP) isoenzymes 3A4 (CYP3A4), 2C9 (CYP2C9), and 2C19 (CYP2C19). THC and CBD inhibit CYP2C- and CYP3A4-mediated metabolism, which may increase exposure to co-administered drugs and cannabinoids themselves, thereby raising the risk of adverse effects in patients receiving polypharmacy or concomitant enzyme-modifying agents [184,185]. Experimental and clinical pharmacokinetic studies further demonstrate that both cannabinoids can alter CYP450 activity and produce measurable changes in drug exposure, supporting the potential for clinically significant interactions, particularly with medications characterized by a narrow therapeutic index [172,184]. In oncology settings, CBD may additionally modify the metabolism of anticancer agents processed via CYP450 enzymes, potentially increasing toxicity or reducing therapeutic efficacy when administered concurrently with standard cancer therapies [171].

DISCUSSION

The available evidence suggests that cannabinoids and the ECS represent a promising but not yet fully validated area of supportive oncology and translational cancer research [7,10,12]. Current clinical data most strongly support the use of cannabinoid-based therapies in the management of chemotherapy-induced nausea and vomiting [17–31], while more limited and heterogeneous evidence exists for cancer-related pain [59–81,91–99], appetite stimulation [32–36], sleep disturbances [37–44], fatigue [45–48], anxiety, and depression [100–106]. Although some patients may experience clinically meaningful symptom relief, the magnitude of benefit remains variable, and cannabinoids cannot currently be considered first-line therapies in most oncological settings [80,95,97–99].

At the same time, extensive preclinical research indicates that cannabinoid signaling may influence multiple biological processes involved in tumor progression, including proliferation, apoptosis, autophagy, endoplasmic reticulum stress, angiogenesis, invasion, oxidative stress, and immune regulation [119–140,144–163]. However, these findings are derived predominantly from in vitro studies and animal models, and robust clinical evidence confirming anticancer efficacy in humans is currently lacking [128,141–143]. Furthermore, the immunomodulatory properties of the ECS appear to be highly context-dependent and may exert both pro- and anti-tumor effects depending on tumor type, receptor expression, and characteristics of the tumor microenvironment [118,125,126,154,160,164,165].

Importantly, cannabinoid-based therapies are associated with dose-dependent adverse effects and clinically relevant drug-drug interactions, which are particularly relevant in oncology patients frequently exposed to polypharmacy and complex treatment regimens [166,168,170,172,180–185]. Consequently, further large-scale, well-designed clinical trials are required to better define the efficacy, safety, optimal indications, and long-term clinical relevance of cannabinoids in oncology [7,99,106].

Limitations

The main limitation of this review is the highly heterogeneous evidence base on cannabinoids in oncology. Clinical evidence is most convincing primarily for chemotherapy induced nausea and vomiting. For other areas of supportive care, including cancer related pain, appetite loss, sleep disturbances, fatigue, anxiety, and depression, the available data remain limited and do not support cannabinoids as first line therapy.

A second limitation concerns the section on possible anticancer effects. Most data on the effects of cannabinoids on apoptosis, autophagy, oxidative stress, angiogenesis, tumor invasion, and the tumor microenvironment are derived from cell culture studies and animal models. These findings have mechanistic significance but do not prove the anticancer efficacy of cannabinoids in patients.

In addition, the included studies differ in the type of cannabinoid preparation, THC to CBD ratio, dose, route of administration, treatment duration, cancer type, and clinical outcomes. This limits direct comparison of results and does not allow uniform clinical recommendations on the use of cannabinoids in oncology.

CONCLUSIONS

Cannabinoids and the endocannabinoid system represent an important and evolving area of oncology research. The strongest current evidence supports the use of cannabinoid-based therapies in supportive cancer care, particularly for chemotherapy-induced nausea and vomiting, rather than as direct anticancer treatment. Evidence for cancer-related pain, appetite stimulation, sleep disturbances, fatigue, anxiety, depression, and other supportive indications remains more limited, heterogeneous, and dependent on individual patient characteristics.

Preclinical studies indicate that cannabinoids may influence multiple biological processes involved in tumor development and progression, including apoptosis, autophagy, endoplasmic reticulum stress, oxidative stress, angiogenesis, invasion, the tumor microenvironment, and immune regulation. However, these findings are derived predominantly from in vitro studies and animal models and have not been translated into convincing clinical evidence demonstrating anticancer efficacy in humans. Therefore, cannabinoids should not currently be considered standard anticancer therapy.

Clinical use of cannabinoids in oncology requires careful consideration of dose-dependent adverse effects and clinically relevant drug-drug interactions, particularly CYP450-mediated interactions, in patients receiving polypharmacy and complex anticancer treatment regimens. Further well-designed randomized clinical trials are needed to better define the efficacy, safety, optimal indications, dosing strategies, and long-term clinical relevance of cannabinoid-based therapies in oncology, and to determine whether promising preclinical findings can be translated into meaningful clinical benefit for cancer patients.

DISCLOSURE

Author Contributions

Conceptualization: Magdalena Korba. Methodology: Magdalena Korba, Izabela Staszczyk. Investigation and data collection: Magdalena Korba, Aleksandra Piętak. Formal analysis: Roksana Hashemi. Writing - original draft: Magdalena Korba, Aleksandra Piętak. Writing - review and editing: Izabela Staszczyk, Roksana Hashemi.

All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

The article did not receive any funding.

Conflict of Interest

The authors declare no conflict of interest.

Use of Artificial Intelligence

The authors used artificial intelligence tools to assist with language editing and structural refinement of the manuscript. All AI-generated content was carefully reviewed and revised by the authors to ensure accuracy and that it did not affect the scientific integrity or substantive content of the work.

REFERENCES

1. Brito Siqueira ALG de, Cremasco PVV, Bahú JO et al. Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection. J Tradit Complement Med 2023;13(6):575–87. https://doi.org/10.1016/j.jtcme.2023.08.006
2. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci 2018;19(3):833. https://doi.org/10.3390/IJMS19030833
3. Lu HC, MacKie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry 2016;79(7):516–25. https://doi.org/10.1016/j.biopsych.2015.07.028
4. Galiègue S, Mary S, Marchand J et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995;232(1):54–61. https://doi.org/10.1111/J.1432-1033.1995.TB20780.X
5. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365(6441):61–5. https://doi.org/10.1038/365061A0
6. Herkenham M, Lynn AB, Little MD et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87(5):1932–6. https://doi.org/10.1073/PNAS.87.5.1932
7. Whiting PF, Wolff RF, Deshpande S et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 2015;313(24):2456–73. https://doi.org/10.1001/JAMA.2015.6358
8. Pacher P, Bátkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol Rev 2006;58(3):389. https://doi.org/10.1124/PR.58.3.2
9. Klimkiewicz A, Jasinska A. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Psychiatria 2017;15(2):88–92. https://doi.org/10.17226/24625
10. Guzmán M. Cannabinoids: potential anticancer agents. Nat Rev Cancer 2003;3(10):745–55. https://doi.org/10.1038/NRC1188
11. Velasco G, Sánchez C, Guzmán M. Anticancer mechanisms of cannabinoids. Curr Oncol 2016;23(2):S23–32. https://doi.org/10.3747/CO.23.3080
12. Abrams DI. Integrating cannabis into clinical cancer care. Curr Oncol 2016;23(2):S8–14. https://doi.org/10.3747/CO.23.3099
13. Lotfi-Jam K, Carey M, Jefford M et al. Nonpharmacologic strategies for managing common chemotherapy adverse effects: a systematic review. J Clin Oncol 2008;26(34):5618–29. https://doi.org/10.1200/JCO.2007.15.9053
14. Wagland R, Richardson A, Armes J et al. Treatment-related problems experienced by cancer patients undergoing chemotherapy: a scoping review. Eur J Cancer Care (Engl) 2015;24(5):605–17. https://doi.org/10.1111/ECC.12246
15. Yeo W, Mo FHK, Yip CCH et al. Quality of Life Associated with Nausea and Vomiting from Anthracycline‐Based Chemotherapy: A Pooled Data Analysis from Three Prospective Trials. Oncologist 2021;26(12):e2288. https://doi.org/10.1002/ONCO.13978
16. Yoshikawa K, Higashijima J, Okitsu H et al. Effects of chemotherapy on quality of life and night-time sleep of colon cancer patients. J Med Invest 2020;67(3.4):338–42. https://doi.org/10.2152/JMI.67.338
17. Sickle MD Van, Oland LD, Ho W et al. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 2001;121(4):767–74. https://doi.org/10.1053/gast.2001.28466
18. Sickle MD Van, Oland LD, Mackie K et al. Delta9-tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol 2003;285(3):566–76. https://doi.org/10.1152/AJPGI.00113.2003
19. Katona I, Freund TF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 2012;35:529–58. https://doi.org/10.1146/ANNUREV-NEURO-062111-150420
20. Kreitzer AC, Carter AG, Regehr WG. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 2002;34(5):787–96. https://doi.org/10.1016/S0896-6273(02)00695-5
21. Browning KN. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015;9(OCT):413. https://doi.org/10.3389/FNINS.2015.00413
22. Derbenev A V., Stuart TC, Smith BN. Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve. J Physiol 2004;559(Pt 3):923. https://doi.org/10.1113/JPHYSIOL.2004.067470
23. Burdyga G, Varro A, Dimaline R et al. Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. Am J Physiol Gastrointest Liver Physiol 2010;299(1):G63. https://doi.org/10.1152/AJPGI.00059.2010
24. Dipatrizio N V. Endocannabinoids in the Gut. Cannabis Cannabinoid Res 2016;1(1):67. https://doi.org/10.1089/CAN.2016.0001
25. Sharkey KA, Wiley JW. The role of the endocannabinoid system in the brain-gut axis. Gastroenterology 2016;151(2):252. https://doi.org/10.1053/J.GASTRO.2016.04.015
26. Sallan SE, Zinberg NE, Frei E. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975;293(16):795–7. https://doi.org/10.1056/NEJM197510162931603
27. May MB, Glode AE. Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Manag Res 2016;8:49. https://doi.org/10.2147/CMAR.S81425
28. Cunningham D, Bradley CJ, Forrest GJ et al. A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues. Eur J Cancer Clin Oncol 1988;24(4):685–9. https://doi.org/10.1016/0277-5379(88)90300-8
29. Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 1986;61(5):502–5. https://doi.org/10.1136/ADC.61.5.502
30. Einhorn LH, Nagy C, Furnas B et al. Nabilone: An Effective Antiemetic in Patients Receiving Cancer Chemotherapy. J Clin Pharmacol 1981;21(1 S):64S-69S. https://doi.org/10.1002/J.1552-4604.1981.TB02576.X
31. Lane M, Vogel CL, Ferguson J et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage 1991;6(6):352–9. https://doi.org/10.1016/0885-3924(91)90026-Z
32. Wheeler EC, Choi P, Howitt J De et al. Cannabis Sativa targets mediobasal hypothalamic neurons to stimulate appetite. Sci Rep 2023;13(1):22970. https://doi.org/10.1038/s41598-023-50112-5
33. Brunt TM, Bossong MG. The neuropharmacology of cannabinoid receptor ligands in central signaling pathways. Eur J Neurosci 2020;55(4):909. https://doi.org/10.1111/EJN.14982
34. PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Cannabis and Cannabinoids (PDQ®). PDQ Cancer Information Summaries 16 Mar. 2011. https://www.ncbi.nlm.nih.gov/books/NBK65755/
35. Jatoi A, Windschitl HE, Loprinzi CL et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 2002;20(2):567–73. https://doi.org/10.1200/JCO.2002.20.2.567
36. Simon L, Baldwin C, Kalea AZ et al. Cannabinoid interventions for improving cachexia outcomes in cancer: a systematic review and meta‐analysis. J Cachexia Sarcopenia Muscle 2021;13(1):23. https://doi.org/10.1002/JCSM.12861
37. Busquets-Garcia A, Bains J, Marsicano G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacology 2017;43(1):4. https://doi.org/10.1038/NPP.2017.206
38. Chen ML, Yu CT, Yang CH. Sleep disturbances and quality of life in lung cancer patients undergoing chemotherapy. Lung Cancer 2008;62(3):391–400. https://doi.org/10.1016/j.lungcan.2008.03.016
39. Nicholson AN, Turner C, Stone BM et al. Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol 2004;24(3):305–13. https://doi.org/10.1097/01.JCP.0000125688.05091.8F
40. Suraev A, McGregor IS, McCartney D et al. Acute Effects of Oral Cannabinoids on Sleep and High‐Density EEG in Insomnia: A Pilot Randomised Controlled Trial. J Sleep Res 2025;35(1):e70124. https://doi.org/10.1111/JSR.70124
41. Hirvonen J, Goodwin RS, Li CT et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 2012;17(6):642–9. https://doi.org/10.1038/MP.2011.82
42. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep 2017;19(4):23. https://doi.org/10.1007/s11920-017-0775-9
43. Zhou ES, Nayak MM, Chai PR et al. Cancer patient’s attitudes of using medicinal cannabis for sleep. J Psychosoc Oncol 2021;40(3):397. https://doi.org/10.1080/07347332.2021.1910396
44. Reddy AC, Hampton JM, Park SJ et al. The effects of tetrahydrocannabinol and cannabidiol on sleep in cancer patients. Clin Transl Oncol 2025;28(4):1431–43. https://doi.org/10.1007/S12094-025-04069-8
45. Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: Mechanisms, contributing factors, and treatment implications. Brain Behav Immun 2012;30(0):S48. https://doi.org/10.1016/J.BBI.2012.06.011
46. Bathula PP, Maciver MB. Cannabinoids in Treating Chemotherapy-Induced Nausea and Vomiting, Cancer-Associated Pain, and Tumor Growth. Int J Mol Sci 2023;25(1):74. https://doi.org/10.3390/IJMS25010074
47. Aviram J, Lewitus GM, Vysotski Y et al. The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients. Front Pain Res (Lausanne) 2022;3. https://doi.org/10.3389/FPAIN.2022.861037
48. Gurgenci T, Hardy J, Huggett G et al. Medicinal Cannabis (MedCan 3): a randomised, multicentre, double-blind, placebo-controlled trial to assess THC/CBD (1:20) to relieve symptom burden in patients with cancer—a study protocol for a randomised controlled trial. Trials 2024;25(1):293. https://doi.org/10.1186/S13063-024-08091-Z
49. Varrassi G, Paladini A, Tran Y Van et al. Advances in the Pathophysiology and Management of Cancer Pain: A Scoping Review. Cancers (Basel) 2026;18(2):259. https://doi.org/10.3390/CANCERS18020259
50. Edwards HL, Mulvey MR, Bennett MI. Cancer-Related Neuropathic Pain. Cancers (Basel) 2019;11(3):373. https://doi.org/10.3390/CANCERS11030373
51. Zhao XX, Cui M, Geng YH et al. A systematic review and meta-analysis of randomized controlled trials of palliative care for pain among Chinese adults with cancer. BMC Palliat Care 2019;18(1):69. https://doi.org/10.1186/S12904-019-0456-Z
52. Evenepoel M, Haenen V, Baerdemaecker T De et al. Pain Prevalence During Cancer Treatment: A Systematic Review and Meta-Analysis. J Pain Symptom Manage 2022;63(3):e317–35. https://doi.org/10.1016/J.JPAINSYMMAN.2021.09.011
53. Fallon M, Giusti R, Aielli F et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018;29(Suppl 4):iv166–91. https://doi.org/10.1093/annonc/mdy152
54. Paice JA. Cancer pain management and the opioid crisis in America: How to preserve hard-earned gains in improving the quality of cancer pain management. Cancer 2018;124(12):2491–7. https://doi.org/10.1002/CNCR.31303
55. Caraceni A, Hanks G, Kaasa S et al. Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncol 2012;13(2). https://doi.org/10.1016/S1470-2045(12)70040-2
56. Wiffen PJ, Wee B, Derry S et al. Opioids for cancer pain - an overview of Cochrane reviews. Cochrane Database Syst Rev 2017;2017(3):CD012592. https://doi.org/10.1002/14651858.CD012592
57. Snijders RAH, Brom L, Theunissen M et al. Update on Prevalence of Pain in Patients with Cancer 2022: A Systematic Literature Review and Meta-Analysis. Cancers (Basel) 2023;15(3):591. https://doi.org/10.3390/CANCERS15030591
58. Shrestha S, Sapkota S, Teoh SL et al. Comprehensive assessment of pain characteristics, quality of life, and pain management in cancer patients: a multi-center cross-sectional study. Qual Life Res 2024;33(10):2755. https://doi.org/10.1007/S11136-024-03725-W
59. Kendall DA, Yudowski GA. Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front Cell Neurosci 2017;10:294. https://doi.org/10.3389/FNCEL.2016.00294
60. Zhang M, Wang T, Meng F et al. The endocannabinoid system in the brain undergoes long-lasting changes following neuropathic pain. iScience 2024;27(12):111409. https://doi.org/10.1016/j.isci.2024.111409
61. Martinez Ramirez CE, Ruiz-Pérez G, Stollenwerk TM et al. Endocannabinoid signaling in the central nervous system. Glia 2023;71(1):5–35. https://doi.org/10.1002/GLIA.24280
62. Gregg LC, Jung KM, Spradley JM et al. Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia. J Neurosci 2012;32(28):9457–68. https://doi.org/10.1523/JNEUROSCI.0013-12.2012
63. Hohmann AG, Suplita RL, Bolton NM et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 2005;435(7045):1108–12. https://doi.org/10.1038/NATURE03658
64. Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 2001;29(3):717–27. https://doi.org/10.1016/S0896-6273(01)00246-X
65. Ohno-Shosaku T, Maejima T, Kano M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 2001;29(3):729–38. https://doi.org/10.1016/S0896-6273(01)00247-1
66. Gutierrez T, Farthing JN, Zvonok AM et al. Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis. Br J Pharmacol 2006;150(2):153. https://doi.org/10.1038/SJ.BJP.0706984
67. Hsieh GC, Pai M, Chandran P et al. Central and peripheral sites of action for CB₂ receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br J Pharmacol 2011;162(2):428–40. https://doi.org/10.1111/J.1476-5381.2010.01046.X
68. Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 2007;153(2):319. https://doi.org/10.1038/SJ.BJP.0707531
69. Finn DP, Haroutounian S, Hohmann AG et al. Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies. Pain 2021;162(Suppl 1):S5–25. https://doi.org/10.1097/J.PAIN.0000000000002268
70. Yang F, Xu Q, Shu B et al. Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation. Pain 2016;157(11):2582–93. https://doi.org/10.1097/J.PAIN.0000000000000680
71. Zhai X, Sarkar PR, Hill KP. Therapeutic use of cannabis and cannabinoids: benefits and risks. Pol Arch Intern Med 2025;135(11). https://doi.org/10.20452/PAMW.17117
72. Maatuf Y, Iskimov A, Binshtok AM et al. The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels. Neuropsychopharmacology 2026 21 Jan. 2026:1–9. https://doi.org/10.1038/s41386-026-02355-9
73. Luz-Veiga M, Azevedo-Silva J, Fernandes JC. Beyond Pain Relief: A Review on Cannabidiol Potential in Medical Therapies. Pharmaceuticals 2023;16(2):155. https://doi.org/10.3390/PH16020155
74. Martinez Naya N, Kelly J, Corna G et al. Molecular and Cellular Mechanisms of Action of Cannabidiol. Molecules 2023;28(16):5980. https://doi.org/10.3390/MOLECULES28165980
75. Sermet S, Li J, Bach A et al. Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes. Toxicology 2021;464. https://doi.org/10.1016/j.tox.2021.153016
76. Nichols JM, Kaplan BLF. Immune Responses Regulated by Cannabidiol. Cannabis Cannabinoid Res 2020;5(1):12. https://doi.org/10.1089/CAN.2018.0073
77. Englund A, Freeman TP, Murray RM et al. Can we make cannabis safer? Lancet Psychiatry 2017;4(8):643–8. https://doi.org/10.1016/S2215-0366(17)30075-5
78. Bhattacharyya S, Morrison PD, Fusar-Poli P et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 2010;35(3):764–74. https://doi.org/10.1038/NPP.2009.184
79. Wang L, Hong PJ, May C et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: A systematic review and meta-analysis of randomised clinical trials. BMJ 2021;374. https://doi.org/10.1136/bmj.n1034
80. Mücke M, Phillips T, Radbruch L et al. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018;2018(3). https://doi.org/10.1002/14651858.CD012182.pub2
81. Bialas P, Fitzcharles MA, Klose P et al. Long-term observational studies with cannabis-based medicines for chronic non-cancer pain: A systematic review and meta-analysis of effectiveness and safety. Eur J Pain 2022;26(6):1221–33. https://doi.org/10.1002/EJP.1957
82. Urch CE, Dickenson AH. Neuropathic pain in cancer. Eur J Cancer 2008;44(8):1091–6. https://doi.org/10.1016/j.ejca.2008.03.015
83. Boland EG, Mulvey MR, Bennett MI. Classification of neuropathic pain in cancer patients. Curr Opin Support Palliat Care 2015;9(2):112–5. https://doi.org/10.1097/SPC.0000000000000136
84. Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist 2010;15 Suppl 2(S2):3–8. https://doi.org/10.1634/THEONCOLOGIST.2009-S505
85. Campbell JN, Meyer RA. Mechanisms of Neuropathic Pain. Neuron 2006;52(1):77. https://doi.org/10.1016/J.NEURON.2006.09.021
86. Rahman W, Dickenson AH. Recent Developments in Neuropathic Pain Mechanisms: Implications for Treatment. Rev Pain 2011;5(2):21. https://doi.org/10.1177/204946371100500204
87. Yoon SY, Oh J. Neuropathic cancer pain: prevalence, pathophysiology, and management. Korean J Intern Med 2018;33(6):1058. https://doi.org/10.3904/KJIM.2018.162
88. Bao H, Wu Z, Wang Q et al. The efficacy of gabapentin combined with opioids for neuropathic cancer pain: a meta-analysis. Transl Cancer Res 2021;10(2):633–44. https://doi.org/10.21037/TCR-20-2692
89. Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review. Palliat Med 2011;25(5):553–9. https://doi.org/10.1177/0269216310378546
90. Kane CM, Mulvey MR, Wright S et al. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med 2018;32(1):276–86. https://doi.org/10.1177/0269216317711826
91. Johal H, Devji T, Chang Y et al. Cannabinoids in Chronic Non-Cancer Pain: A Systematic Review and Meta-Analysis. Clin Med Insights Arthritis Musculoskelet Disord 2020;13. https://doi.org/10.1177/1179544120906461
92. Hansen JS, Gustavsen S, Roshanisefat H et al. Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial. Pharmaceuticals (Basel) 2023;16(8). https://doi.org/10.3390/PH16081079
93. Haney M, Choo TH, Tiersten A et al. Oral Cannabis for Taxane-Induced Neuropathy: A Pilot Randomized Placebo-Controlled Study. Cannabis Cannabinoid Res 2025;10(5). https://doi.org/10.1089/CAN.2025.0028
94. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 2014;47(1):166–73. https://doi.org/10.1016/j.jpainsymman.2013.02.018
95. Busse JW, Vankrunkelsven P, Zeng L et al. Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline. BMJ 2021;374. https://doi.org/10.1136/BMJ.N2040
96. Überall MA. A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain. J Pain Res 2020;13:399–410. https://doi.org/10.2147/JPR.S240011
97. Portenoy RK, Ganae-Motan ED, Allende S et al. Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial. J Pain 2012. https://doi.org/10.1016/j.jpain.2012.01.003
98. Lichtman AH, Lux EA, McQuade R et al. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. J Pain Symptom Manage 2018;55(2):179-188.e1. https://doi.org/10.1016/j.jpainsymman.2017.09.001
99. Häuser W, Welsch P, Radbruch L et al. Cannabis‐based medicines and medical cannabis for adults with cancer pain. Cochrane Database Syst Rev 2023;2023(6):CD014915. https://doi.org/10.1002/14651858.CD014915.PUB2
100. Zhu J, Fang F, Sjölander A et al. First-onset mental disorders after cancer diagnosis and cancer-specific mortality: A nationwide cohort study. Ann Oncol 2017;28(8):1964–9. https://doi.org/10.1093/annonc/mdx265
101. Hirschfeld RMA. The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care. Prim Care Companion J Clin Psychiatry 2001;3(6):244–54. https://doi.org/10.4088/PCC.V03N0609
102. Gallego-Landin I, García-Baos A, Castro-Zavala A et al. Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression. Front Pharmacol 2021;12. https://doi.org/10.3389/FPHAR.2021.762738
103. Reddy AC, Hampton JM, Park SJ et al. Measuring the Effects of Cannabis on Anxiety and Depression Among Cancer Patients. Cancer Med 2025;14(21). https://doi.org/10.1002/CAM4.71342
104. Hu S, Lin A, Luo P et al. Association of cannabis use with depression among cancer patients. Prev Med Rep 2023;35. https://doi.org/10.1016/j.pmedr.2023.102304
105. Nayak MM, Chai P, Catalano PJ et al. Cannabidiol for Scan-Related Anxiety in Women With Advanced Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open 2024;7(12). https://doi.org/10.1001/JAMANETWORKOPEN.2024.50391
106. Crichton M, Dissanayaka T, Marx W et al. Does medicinal cannabis affect depression, anxiety, and stress in people with cancer? A systematic review and meta-analysis of intervention studies. Maturitas 2024;184. https://doi.org/10.1016/j.maturitas.2024.107941
107. Harris CS, Kober KM, Conley YP et al. Symptom Clusters in Patients Receiving Chemotherapy: A Systematic Review. BMJ Support Palliat Care 2021;12(1):10. https://doi.org/10.1136/BMJSPCARE-2021-003325
108. Kwekkeboom KL, Cherwin CH, Lee JW et al. Mind-Body Treatments for the Pain-Fatigue-Sleep Disturbance Symptom Cluster in Persons with Cancer. J Pain Symptom Manage 2009;39(1):126. https://doi.org/10.1016/J.JPAINSYMMAN.2009.05.022
109. Dodd MJ, Cho MH, Cooper BA et al. The effect of symptom clusters on functional status and quality of life in women with breast cancer. Eur J Oncol Nurs 2009;14(2):101. https://doi.org/10.1016/J.EJON.2009.09.005
110. Ward Sullivan C, Leutwyler H, Dunn LB et al. A Review of the Literature on Symptom Clusters in Studies That Included Oncology Patients Receiving Primary or Adjuvant Chemotherapy. J Clin Nurs 2017;27(3–4):516. https://doi.org/10.1111/JOCN.14057
111. Harris CS, Kober K, Cooper B et al. Symptom clusters in oncology outpatients: stability and consistency across a cycle of chemotherapy. BMJ Support Palliat Care 2024;13(e3):E1198–211. https://doi.org/10.1136/SPCARE-2022-003785
112. Lynch Kelly D, Dickinson K, Hsiao CP et al. Biological Basis for the Clustering of Symptoms. Semin Oncol Nurs 2016;32(4):351. https://doi.org/10.1016/J.SONCN.2016.08.002
113. Rha SY, Lee J. Stable Symptom Clusters and Evolving Symptom Networks in Relation to Chemotherapy Cycles. J Pain Symptom Manage 2021;61(3):544–54. https://doi.org/10.1016/j.jpainsymman.2020.08.008
114. Kwekkeboom KL, Wieben A, Braithwaite L et al. Characteristics of Cancer Symptom Clusters Reported Through A Patient-Centered Symptom Cluster Assessment. West J Nurs Res 2021;44(7):662. https://doi.org/10.1177/01939459211012426
115. Kwekkeboom K, Zhang Y, Campbell T et al. Randomized controlled trial of a brief cognitive-behavioral strategies intervention for the pain, fatigue, and sleep disturbance symptom cluster in advanced cancer. Psychooncology 2018;27(12):2761–9. https://doi.org/10.1002/PON.4883
116. So WKW, Law BMH, Ng MSN et al. Symptom clusters experienced by breast cancer patients at various treatment stages: A systematic review. Cancer Med 2021;10(8):2531. https://doi.org/10.1002/CAM4.3794
117. Creangă-Murariu I, Rezuș II, Karami R et al. Indications of Cannabinoids for the Palliation of Cancer-Associated Symptoms: A Systematic Review and Meta-Analysis. Curr Oncol Rep 2025;27(9):1080–96. https://doi.org/10.1007/S11912-025-01695-X
118. Kienzl M, Kargl J, Schicho R. The Immune Endocannabinoid System of the Tumor Microenvironment. Int J Mol Sci 2020;21(23):1–25. https://doi.org/10.3390/IJMS21238929
119. Costas-Insua C, Guzmán M. Endocannabinoid signaling in glioma. Glia 2022;71(1):127. https://doi.org/10.1002/GLIA.24173
120. Ellert-Miklaszewska A, Ciechomska IA, Kaminska B. Cannabinoid Signaling in Glioma Cells. Adv Exp Med Biol 2020;1202:223–41. https://doi.org/10.1007/978-3-030-30651-9_11
121. Dumitru CA, Sandalcioglu IE, Karsak M. Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs. Front Mol Neurosci 2018;11. https://doi.org/10.3389/FNMOL.2018.00159
122. Calatozzolo C, Salmaggi A, Pollo B et al. Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurol Sci 2007;28(6):304–10. https://doi.org/10.1007/S10072-007-0843-8
123. Jesús ML De, Hostalot C, Garibi JM et al. Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas. Neurochem Int 2010;56(6–7):829–33. https://doi.org/10.1016/j.neuint.2010.03.007
124. Schley M, Ständer S, Kerner J et al. Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res Bull 2009;79(5):333–7. https://doi.org/10.1016/j.brainresbull.2009.01.011
125. Wu X, Han L, Zhang X et al. Alteration of endocannabinoid system in human gliomas. J Neurochem 2012;120(5):842–9. https://doi.org/10.1111/J.1471-4159.2011.07625.X
126. Ellert-Miklaszewska A, Grajkowska W, Gabrusiewicz K et al. Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res 2007;1137(1):161–9. https://doi.org/10.1016/j.brainres.2006.12.060
127. Hashemi M, Bashi S, Zali A. The expression level of cannabinoid receptors type 1 and 2 in the different types of astrocytomas. Mol Biol Rep 2020;47(7):5461–7. https://doi.org/10.1007/S11033-020-05636-8
128. Guzmán M, Duarte MJ, Blázquez C et al. A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 2006;95(2):197. https://doi.org/10.1038/SJ.BJC.6603236
129. Stock K, Kumar J, Synowitz M et al. Neural precursor cells induce cell death of high-grade astrocytomas via stimulation of TRPV1. Nat Med 2012;18(8):1232. https://doi.org/10.1038/NM.2827
130. Markouli M, Strepkos D, Papavassiliou AG et al. Targeting of endoplasmic reticulum (ER) stress in gliomas. Pharmacol Res 2020;157. https://doi.org/10.1016/j.phrs.2020.104823
131. Galve-Roperh I, Sánchez C, Cortés ML et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 2000;6(3):313–9. https://doi.org/10.1038/73171
132. Carracedo A, Lorente M, Egia A et al. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 2006;9(4):301–12. https://doi.org/10.1016/j.ccr.2006.03.005
133. Cudaback E, Marrs W, Moeller T et al. The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas. PLoS One 2010;5(1). https://doi.org/10.1371/JOURNAL.PONE.0008702
134. Salazar M, Carracedo A, Salanueva ÍJ et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 2009;119(5):1359–72. https://doi.org/10.1172/JCI37948
135. Wang K, Wang Q, Li Q et al. Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways. Biomed Res Int 2021;2021. https://doi.org/10.1155/2021/6612592
136. Krones-Herzig A, Mittal S, Yule K et al. Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53. Cancer Res 2005;65(12):5133–43. https://doi.org/10.1158/0008-5472.CAN-04-3742
137. Bouaboula M, Bourrié B, Rinaldi-Carmona M et al. Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J Biol Chem 1995;270(23):13973–80. https://doi.org/10.1074/jbc.270.23.13973
138. Blázquez C, Casanova ML, Planas A et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J 2003;17(3):529–31. https://doi.org/10.1096/FJ.02-0795FJE
139. Blázquez C, Salazar M, Carracedo A et al. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 2008;68(6):1945–52. https://doi.org/10.1158/0008-5472.CAN-07-5176
140. Ramer R, Hinz B. Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 2008;100(1):59–69. https://doi.org/10.1093/JNCI/DJM268
141. Singh K, Jamshidi N, Zomer R et al. Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies. Int J Mol Sci 2020;21(17):1–15. https://doi.org/10.3390/IJMS21176265
142. Cridge BJ, Rosengren RJ. Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag Res 2013;5(1):301–13. https://doi.org/10.2147/CMAR.S36105
143. Mangal N, Erridge S, Habib N et al. Cannabinoids in the landscape of cancer. J Cancer Res Clin Oncol 2021;147(9):2507–34. https://doi.org/10.1007/S00432-021-03710-7
144. McAllister SD, Murase R, Christian RT et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 2010;129(1):37. https://doi.org/10.1007/S10549-010-1177-4
145. Salles ÉL, Naeini SE, Khodadadi H et al. Inhalant cannabidiol impedes tumor growth through decreased tumor stemness and impaired angiogenic switch in NCI-H1437-induced human lung cancer model. Hum Cell 2023;36(3):1204–10. https://doi.org/10.1007/S13577-023-00869-8
146. Jeon Y, Kim T, Kwon H et al. Cannabidiol potentiates p53-driven autophagic cell death in non-small cell lung cancer following DNA damage: a novel synergistic approach beyond canonical pathways. Exp Mol Med 2025;57(5):979–89. https://doi.org/10.1038/S12276-025-01444-X
147. Hamad H, Olsen BB. Cannabidiol Induces Cell Death in Human Lung Cancer Cells and Cancer Stem Cells. Pharmaceuticals (Basel) 2021;14(11). https://doi.org/10.3390/PH14111169
148. Fisher T, Golan H, Schiby G et al. In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma. Curr Oncol 2016;23(Suppl 2):S15. https://doi.org/10.3747/CO.23.2893
149. Alharris E, Singh NP, Nagarkatti PS et al. Role of miRNA in the regulation of cannabidiol-mediated apoptosis in neuroblastoma cells. Oncotarget 2019;10(1):45–59. https://doi.org/10.18632/ONCOTARGET.26534
150. McKallip RJ, Jia W, Schlomer J et al. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 2006;70(3):897–908. https://doi.org/10.1124/MOL.106.023937
151. Gallily R, Even-Chen T, Katzavian G et al. Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma 2003;44(10):1767–73. https://doi.org/10.1080/1042819031000103917
152. Jia W, Hegde VL, Singh NP et al. Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Mol Cancer Res 2006;4(8):549–62. https://doi.org/10.1158/1541-7786.MCR-05-0193
153. Besser E, Gelfand A, Procaccia S et al. Cannabinoid combination targets NOTCH1-mutated T-cell acute lymphoblastic leukemia through the integrated stress response pathway. Elife 2024;12. https://doi.org/10.7554/ELIFE.90854
154. Sarsembayeva A, Kienzl M, Gruden E et al. 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. Front Immunol 2023;13. https://doi.org/10.3389/FIMMU.2022.997115
155. Ghosh S, Preet A, Groopman JE et al. Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. Mol Immunol 2006;43(14):2169–79. https://doi.org/10.1016/j.molimm.2006.01.005
156. Robinson RH, Meissler JJ, Fan X et al. A CB2-Selective Cannabinoid Suppresses T-Cell Activities and Increases Tregs and IL-10. J Neuroimmune Pharmacol 2015;10(2):318–32. https://doi.org/10.1007/S11481-015-9611-3
157. Rajesh M, Mukhopadhyay P, Haskó G et al. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 2008;153(2):347–57. https://doi.org/10.1038/SJ.BJP.0707569
158. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19(11):1423–37. https://doi.org/10.1038/NM.3394
159. Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res 2019;79(18):4557–67. https://doi.org/10.1158/0008-5472.CAN-18-3962
160. Carlisle SJ, Marciano-Cabral F, Staab A et al. Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2002;2(1):69–82. https://doi.org/10.1016/S1567-5769(01)00147-3
161. Tomić S, Joksimović B, Bekić M et al. Prostaglanin-E2 Potentiates the Suppressive Functions of Human Mononuclear Myeloid-Derived Suppressor Cells and Increases Their Capacity to Expand IL-10-Producing Regulatory T Cell Subsets. Front Immunol 2019;10(MAR). https://doi.org/10.3389/FIMMU.2019.00475
162. Lee CR, Kwak Y, Yang T et al. Myeloid-Derived Suppressor Cells Are Controlled by Regulatory T Cells via TGF-β during Murine Colitis. Cell Rep 2016;17(12):3219–32. https://doi.org/10.1016/J.CELREP.2016.11.062
163. Swatler J, Ju YJ, Anderson AC et al. Tumors recycle glucocorticoids to drive Treg-mediated immunosuppression. J Clin Invest 2023;133(18). https://doi.org/10.1172/JCI173141
164. Held-Feindt J, Dörner L, Sahan G et al. Cannabinoid receptors in human astroglial tumors. J Neurochem 2006;98(3):886–93. https://doi.org/10.1111/J.1471-4159.2006.03911.X
165. Martínez-Martínez E, Gómez I, Martín P et al. Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival. Oncoscience 2015;2(2):131–41. https://doi.org/10.18632/ONCOSCIENCE.119
166. Herdegen T, Cascorbi I. Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs. Dtsch Arztebl Int 2023;120(49):833–40. https://doi.org/10.3238/ARZTEBL.M2023.0223
167. Clarke S, Butcher BE, McLachlan AJ et al. Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain. PLoS One 2022;17(10). https://doi.org/10.1371/JOURNAL.PONE.0270543
168. Johnson JR, Burnell-Nugent M, Lossignol D et al. Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain. J Pain Symptom Manage 2010;39(2):167–79. https://doi.org/10.1016/j.jpainsymman.2009.06.008
169. Ganesh S, Cortes-Briones J, Schnakenberg Martin AM et al. Delta-9-Tetrahydrocannabinol, Cannabidiol, and Acute Psychotomimetic States: A Balancing Act of the Principal Phyto-Cannabinoids on Human Brain and Behavior. Cannabis Cannabinoid Res 2023;8(5):846–56. https://doi.org/10.1089/CAN.2021.0166
170. Velayudhan L, McGoohan K, Bhattacharyya S. Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis. PLoS Med 2021;18(3). https://doi.org/10.1371/JOURNAL.PMED.1003524
171. Rein JL, Zeng H, Faulkner GB et al. A Retrospective Cohort Study That Examined the Impact of Cannabis Consumption on Long-Term Kidney Outcomes. Cannabis Cannabinoid Res 2024;9(2):635–45. https://doi.org/10.1089/CAN.2022.0141
172. Doohan PT, Oldfield LD, Arnold JC et al. Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization. AAPS J 2021;23(4). https://doi.org/10.1208/S12248-021-00616-7
173. Watanabe AH, Navaravong L, Sirilak T et al. A systematic review and meta-analysis of randomized controlled trials of cardiovascular toxicity of medical cannabinoids. J Am Pharm Assoc 2021;61(5):e1–13. https://doi.org/10.1016/j.japh.2021.03.013
174. Theerasuwipakorn N, Prechawat S, Chokesuwattanaskul R et al. Cannabis and adverse cardiovascular events: A systematic review and meta-analysis of observational studies. Toxicol Rep 2023;10:537–43. https://doi.org/10.1016/j.toxrep.2023.04.011
175. Storck W, Elbaz M, Vindis C et al. Cardiovascular risk associated with the use of cannabis and cannabinoids: a systematic review and meta-analysis. Heart 2025;111(22):1047–56. https://doi.org/10.1136/HEARTJNL-2024-325429
176. Steur SJ van der, Batalla A, Bossong MG. Factors Moderating the Association between Cannabis Use and Psychosis Risk: A Systematic Review. Brain Sci 2020;10(2):97. https://doi.org/10.3390/BRAINSCI10020097
177. Burke C, Freeman TP, Sallis H et al. Associations of cannabis use, tobacco use, and incident anxiety, mood, and psychotic disorders: a systematic review and meta-analysis. Psychol Med 2024;54(15):4287–301. https://doi.org/10.1017/S0033291724002587
178. Hindley G, Beck K, Borgan F et al. Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis. Lancet Psychiatry 2020;7(4):344–53. https://doi.org/10.1016/S2215-0366(20)30074-2
179. Nielsen S, Picco L, Murnion B et al. Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies. Neuropsychopharmacology 2022;47(7):1315. https://doi.org/10.1038/S41386-022-01322-4
180. Bergmann KR, Broekhuizen K, Groeneveld GJ. Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop‐seizure frequency. Br J Clin Pharmacol 2019;86(2):380. https://doi.org/10.1111/BCP.14158
181. Smith SA, Le GH, Teopiz KM et al. Effects of cannabidiol and Δ9-tetrahydrocannabinol on cytochrome P450 enzymes: a systematic review. Drug Metab Rev 2024;56(2):164–74. https://doi.org/10.1080/03602532.2024.2346767
182. Chesney E, Oliver D, Green A et al. Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology 2020;45(11):1799–806. https://doi.org/10.1038/S41386-020-0667-2
183. Bar-Sela G, Cohen I, Campisi-Pinto S et al. Correction: Bar-Sela et al. Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers 2020, 12, 2447. Cancers (Basel) 2022;14(8):1957. https://doi.org/10.3390/CANCERS14081957
184. Bansal S, Zamarripa CA, Spindle TR et al. Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants. Clin Pharmacol Ther 2023;114(3):693–703. https://doi.org/10.1002/CPT.2973
185. Bansal S, Paine MF, Unadkat JD. Comprehensive Predictions of Cytochrome P450 (P450)-Mediated In Vivo Cannabinoid-Drug Interactions Based on Reversible and Time-Dependent P450 Inhibition in Human Liver Microsomes. Drug Metab Dispos 2022;50(4):351–60. https://doi.org/10.1124/dmd.121.000734
186. Florian J, Salcedo P, Burkhart K et al. Cannabidiol and Liver Enzyme Level Elevations in Healthy Adults: A Randomized Clinical Trial. JAMA Intern Med 2025;185(9):1070–8. https://doi.org/10.1001/JAMAINTERNMED.2025.2366

back