CBD Oil And Cancer


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Cannabidiol (CBD) as a Promising Anti-Cancer Drug 1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; Cannabis has been used medicinally for millennia, but has not been approved by the U.S. Food and Drug Administration to treat any medical condition. Cannabinoids are the components in cannabis; some are commercially available to treat symptoms. Get detailed information in this clinician summary.

Cannabidiol (CBD) as a Promising Anti-Cancer Drug

1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; [email protected] (E.S.S.); [email protected] (A.K.W.); [email protected] (D.M.J.)

Andrea K. Watters

1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; [email protected] (E.S.S.); [email protected] (A.K.W.); [email protected] (D.M.J.)

Danny MacKenzie, Jr.

1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; [email protected] (E.S.S.); [email protected] (A.K.W.); [email protected] (D.M.J.)

Lauren M. Granat

2 Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; [email protected]

Dong Zhang

1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; [email protected] (E.S.S.); [email protected] (A.K.W.); [email protected] (D.M.J.)

1 Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA; [email protected] (E.S.S.); [email protected] (A.K.W.); [email protected] (D.M.J.)

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Simple Summary

The use of cannabinoids containing plant extracts as herbal medicine can be traced back to as early as 500 BC. In recent years, the medical and health-related applications of one of the non-psychotic cannabinoids, cannabidiol or CBD, has garnered tremendous attention. In this review, we will discuss the most recent findings that strongly support the further development of CBD as a promising anti-cancer drug.


Recently, cannabinoids, such as cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC), have been the subject of intensive research and heavy scrutiny. Cannabinoids encompass a wide array of organic molecules, including those that are physiologically produced in humans, synthesized in laboratories, and extracted primarily from the Cannabis sativa plant. These organic molecules share similarities in their chemical structures as well as in their protein binding profiles. However, pronounced differences do exist in their mechanisms of action and clinical applications, which will be briefly compared and contrasted in this review. The mechanism of action of CBD and its potential applications in cancer therapy will be the major focus of this review article.

1. Introduction

The use of Cannabis sativa plant extract as herbal medicine can be dated back as early as 500 BC in Asia. The human endocannabinoid system was uncovered after the discovery of the cannabinoid receptors [1]. It was initially thought that cannabinoids produce their physiological effects via non-specific interactions with the cellular membrane; however, research involving rat models in the late-1980s led to the discovery and characterization of specific cannabinoid receptors, CB1 and CB2 [2,3]. The CB1 receptor is expressed throughout the central nervous system (CNS), whereas the CB2 receptor is found primarily in the immune system and hematopoietic cells [4]. Soon after the discovery of CB1 and CB2, their endogenous ligands, or endocannabinoids, were also identified, including 2-arachidonolyglycerol (2-AG) and N-arachidonoylethanolamine (AEA, also called anandamide) ( Figure 1 A, i and ii) [5,6,7,8]. CB1 and CB2 belong to a large family of transmembrane proteins, called G protein-coupled receptors (GPCRs), and are now believed to be responsible for the majority of the physiological effects of the endocannabinoids ( Figure 1 B). Both receptors are coupled with Gαi/o, which can inhibit the adenylyl cyclase (AC) [4,9]. CB1 can also be coupled to Gαq/11 [10] and Gα12/13 [11]. CB2 has also been shown to act through Gαs [12]. For a more in-depth understanding of the downstream effects of the endocannabinoids and their receptors under physiological conditions, we refer you to other excellent reviews on the topic [13,14].

Endocannabinoid system. (A) Chemical structures of two endogenous cannabinoids, 2-arachidonylglycerol (i, 2-AG) and N-arachidonylethanolamine (ii, AEA), and two representative exogenous cannabinoids from Cannabis sativa, cannabidiol (iii, CBD) and Δ 9 -tetrahydrocannabinol (iv, Δ 9 -THC). (B) Schematic diagrams of the signaling transduction pathways of the endocannabinoid system. 2-AG and AEA are agonists of CB1 and CB2. Some of the downstream effects include: (1) upregulation of p42/p44 mitogen-activated protein kinases (MAPKs) by direct inhibition of adenylyl cyclase (AC) and direct activation of phospholipase C (PLC), leading to the induction of neuronal growth, interleukin production, and inflammation. PKA: protein kinase A. PKC: protein kinase C. (2) Activation of p38 MAPK, which induces inflammation and apoptosis. (3) Activation of the phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways. Under certain conditions, these endocannabinoids can also induce transcription, cell survival, proliferation, and differentiation through similar pathways. Additionally, the cannabinoid receptors can also modulate ion channels including G protein-coupled inwardly-rectifying potassium channels (GIRKs) and voltage (V)-gated calcium channels.

The two primary endocannabinoids, 2-AG and AEA, can activate either CB1 or CB2 and are synthesized on-demand from phospholipid precursors in response to an elevation of intracellular calcium [15,16]. In addition to CB1 and CB2, 2-AG and AEA can also bind other transmembrane proteins, including orphan G protein-coupled receptor 55 (GPR55), peroxisome proliferator-activated receptors (PPARs), and transient receptor potential vanilloid (TRPV) channel type 1 (TRPV1) [17,18].

The TRPV channels are of particular interest concerning the anti-tumor functions of cannabidiol (CBD) ( Figure 1 A, iii), which will be discussed in more detail later. Six different TRPV channels have been identified in humans and can be subdivided into two groups: TRPV1, TRPV2, TRPV3, and TRPV4 belong to group I, while TRPV5 and TRPV6 fall into group II [19]. Though the exact functions of the TRPV channels are still under intense investigation, they are likely involved in regulating cellular calcium homeostasis. For example, TRPV1 and TRPV2 can be found in the cytoplasmic membrane as well as the endoplasmic reticulum (ER) membrane. They both play an important role in regulating the cytoplasmic calcium concentration from the extracellular sources as well as the calcium stored within the ER. Disruption of cellular calcium homeostasis can lead to increased production of reactive oxygen species (ROS), ER stress, and cell death.

A variety of cannabinoids exist in the Cannabis sativa plant (also known as the hemp or marijuana plant). There are more than 100 different cannabinoids and Δ 9 –tetrahydrocannabinol (Δ 9 -THC) ( Figure 1 A, iv) and CBD are the most well-known ones. The so called drug-type Cannabis sativa contains higher level of Δ 9 -THC and is used more widely for medical and recreational purposes, whereas the fiber-type cannabis contains less than 0.2% of Δ 9 -THC and is more often used in textiles and food [20,21]. Δ 9 -THC is thought to be the psychotic cannabinoid and many of its psychoactive effects are due to its interaction with the CB1 receptor, whereas its immune-modulatory properties are likely due to its interaction with the CB2 receptor. In contrast, CBD is non-psychoactive and has a relatively low affinity to both CB1 and CB2 [22].

The utility of cannabinoids in the treatment of cancer has long been of great interest. Recently, both CB1 and CB2 were found to be expressed in many cancer types. Intriguingly, both receptors were often undetectable at the site of the cancers’ origin before neoplastic transformation [23]. Additional evidence for the role of endocannabinoid system in neoplasia came when Wang and colleagues showed that CB1 has a tumor-suppressive function in a genetically modified mouse model of colon cancer [24]. On the other hand, CB1 is upregulated in hepatocellular carcinoma and Hodgkin lymphoma, and the extent to which CB1 was overexpressed correlated with disease severity in epithelial ovarian carcinoma [25,26,27]. Similarly, CB2 has also been found to be overexpressed in HER2+ breast cancers and gliomas [28,29]. Finally, it was shown that overexpression of both CB1 and CB2 was correlated with poor prognosis in stage IV colorectal carcinoma [30,31]. In 1976, Carchman and colleagues found that the administration of cannabinoids, such as Δ 8 -THC, Δ 9 -THC, and CBD, inhibited the DNA synthesis and growth of lung adenocarcinoma in cultured cells as well as mouse tumor models [32,33]. Similar effects were seen in both in vitro and in vivo models of various other cancers, including glioma, breast, pancreas, prostate, colorectal carcinoma, and lymphoma [34,35]. There are various proposed mechanisms of action behind these findings, including, but not limited to: cell cycle arrest, induction of apoptosis, as well as inhibition of neovascularization, migration, adhesion, invasion, and metastasis [36]. Despite the multitude of positive results with Δ 9 -THC-related cannabinoids in cancer research, the clinical use of these compounds is limited due to their psychoactive side effects.

In contrast to the Δ 9 -THC-related cannabinoids, CBD has no known psychoactive effects, and therefore, has recently been the focus of intense research in many therapeutic areas, including cancer. At present, the Food and Drug Administration (FDA) has only approved Epidiolex, purified CBD, for use in patients with seizures associated with the Lennox-Gastaut syndrome or Dravet syndrome [37]. Globally, more than 40 countries have approved medical marijuana/cannabis programs, whereas this is true of 34 states in the USA, plus the District of Columbia, Guam, Puerto Rico, and US Virgin Islands. While marijuana is considered a Schedule I controlled substance in the US, the Drug Enforcement Administration ruled that CBD is a Schedule V controlled substance [38]. When approved by the FDA, CBD must contain less than 0.1% of Δ 9 -THC.

It has been noted that CBD has a relatively low affinity to both CB1 and CB2 [22]. However, it was found that CBD can act as an antagonist to CB1 in the mouse vas deferens and brain tissues in vitro [39]. There is also evidence suggesting that CBD may act as an inverse agonist of human CB2 [22]. Other cellular receptors that CBD may interact with include TRPVs, 5-HT1A, GPR55, and PPARγ [40]. It has been hypothesized that CBD has robust anti-proliferative and pro-apoptotic effects. In addition, it may also inhibit cancer cell migration, invasion, and metastasis [1]. The utility of CBD in anti-tumor therapy and the potential mechanisms behind it will be discussed in more detail below. Since much of the anti-tumor activity of CBD seems to hinge on its regulation of ROS, ER stress, and immune modulation, we will first summarize the interplays between ROS, ER stress, and inflammation and their known effects on various aspects of tumorigenesis. Thereafter, we will further discuss the anti-tumor effects of CBD on a variety of cancers and the molecular mechanisms behind them.

2. The Interplays between Reactive Oxygen Species (ROS), ER Stress, Inflammation, and Cancers

2.1. ROS and Cancers

ROS refer to various oxygen-containing species that are energetically unstable and highly reactive with a variety of biomolecules, including amino acids, lipids and nucleic acids. Commonly seen ROS include superoxide (O2 − ), peroxide (O2 −2 ), hydrogen peroxide (H2O2), and hydroxyl free radical (OH − ) [41,42,43,44]. The most common sources of ROS are the electron transport chain in the mitochondria and the NADPH oxidase (NOX) family of transmembrane enzymes ( Figure 2 ). Certain enzymes and organelles, such as peroxisomes and ER, can also produce ROS. ROS can directly oxidize nucleic acids, proteins, and lipids thus altering or disrupting their functions [45].

Origins and effects of cellular reactive oxygen species (ROS). ROS are generated by complex I and III of the electron transport chain in the mitochondria and by NADPH oxidase (NOX) enzymes located at the cytoplasmic membrane (PM). ROS disrupt cellular processes by oxidizing the cysteine (Cys) residues of various proteins and damaging nucleic acids. Oxidation by ROS could cause the inactivation of phosphatases, activation of kinases and transcription factors (TF), and genomic alterations, leading to enhanced cellular proliferation and survival. ROS production is counteracted by the generation of antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), peroxiredoxin (PRX), thioredoxin (TRX), and catalase. In cancers, redox homeostasis is modified to favor ROS tolerance. OM: outer mitochondrial membrane. IM: inner mitochondrial membrane. NM: nuclear membrane.

To prevent constant damage to biomolecules, ROS are counter-balanced by various antioxidants inside the cells. Major anti-oxidant enzymes include superoxide dismutase (SOD), catalase, peroxiredoxin (PRX), thioredoxin (TRX), and glutathione peroxidase (GPX) [42].

In cancers, the redox balance is altered so that increased ROS production favors tumor progression and expansion while evading cell death. The pro-tumor effects of increased ROS generation include, but are not limited to, genomic instability and enhanced proliferation [42,43,44] ( Figure 2 ). ROS damage DNA by oxidizing guanine and forming 8-hydroxyguanine and 8-nitroguanine. This could lead to deletions/insertions, mutations in base pairing, and strand breaks followed by mutagenic repair [44,45]. Genome instability plays a key role in tumor progression through the accumulation of mutations that promote uncontrolled growth and evade cell death [43]. Proliferation is further enhanced through the oxidation and activation of the pro-growth intracellular signaling pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription factor vital for growth and migration, also becomes activated by ROS through inhibiting the phosphorylation of the inhibitor of NF-κB α (IκBα), or through promoting the S-glutathionylation of the inhibitor of NF-κB kinase subunit β (IKKβ). Finally, cancer cells can rewire their signaling transduction pathways to cope with elevated intracellular ROS. Most notably, this can be achieved through increased mitochondrial SOD activity or inactivation of the scavenging enzymes [42,46].

Nonetheless, toxic levels of ROS can induce cell death or autophagy in cancer cells. ROS modulate calcium channels, pumps, and exchangers activity by oxidizing their Cys residues [43]. The increase of intracellular mitochondrial calcium or the oxidation of lipids damages the mitochondrial membrane resulting in the release of cytochrome c, a potent activator of apoptosomes [42,45]. ROS can also directly affect caspase activity and cleavage of Bcl-2, and/or increase the expression of cell death receptors such as TRAIL and Fas [47]. Autophagy can be induced by the activation of the mTOR pathway.

2.2. Endoplasmic Reticulum (ER) Stress and Cancers

ER is an important organelle that plays a critical role in post-translational modification and folding of proteins, calcium homeostasis, and other biological processes [48,49]. Accumulation of unfolded and/or misfolded proteins triggers the unfolded protein response (UPR), which helps to re-balance the ER homeostasis. UPR temporarily halts protein synthesis and attempts to correct and re-fold proteins. In the case that the unfolded and/or misfolded proteins cannot be corrected in time, they will then be targeted for protein degradation.

UPR is a well-studied cellular process ( Figure 3 A). It is primarily regulated by the 78-kDa glucose-regulated protein (GRP78), which is also known as the binding immunoglobulin protein (BiP) [49]. Under non-stress conditions, GRP78 binds and inhibits three transmembrane proteins: inositol-requiring enzymes 1α (IRE1α), pancreatic endoplasmic reticulum kinase (PERK), as well as the activating transcription factor 6 (ATF6) [48,49]. Whereas under ER stress conditions, GRP78 binds the unfolded proteins, dissociates from PERK, IRE1α, and ATF6, and results in the activation of three distinct, but interconnecting, pathways. Downstream of the PERK and ATF6 cascades, CHOP activity is increased.

Endoplasmic reticulum (ER) homeostasis, stress, and the unfolded protein response (UPR). (A) ER homeostasis is mediated by 78-kDa glucose-regulated protein (GRP78). Under stress conditions, GRP78 dissociates from pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzymes 1α (IRE1α), as well as the activating transcription factor 6 (ATF6), leading to activation of their downstream signaling cascades in order to restore ER homeostasis. (B) When ER homeostasis fails to be restored, excessive UPR could lead to apoptosis, primarily via upregulation of C/EBP homologous protein (CHOP). PM: cytoplasmic membrane; eIF2α: eukaryotic initiation factor 2α; ATF4: activating transcription factor 4; GADD34: DNA damage inducible protein 34; XPB1: X-box-binding protein (XBP1s: spliced form); ERO1α: endoplasmic reticulum oxidoreductase 1α; PDI: protein disulfide isomerase; DR5: death receptor 5; TRAIL: TNF related apoptosis-inducing ligand; IP3R: inositol 1,4,5-triphosphate receptor; BAP31: B cell receptor-associated protein 31; Bid: BH3 Interacting Domain Death Agonist; TRAF2: tumor necrosis factor receptor-associated factor 2; RIDD: regulated IRE1-dependent decay; ASK1: apoptosis signal-regulating kinase 1; JNK: JUN N-terminal kinase; E2F7: E2F transcription factor 7; E2F1: E2F transcription factor 1.

CHOP induces apoptosis via multiple pathways ( Figure 3 B): (i) It increases the transcription of GADD34 [49]; (ii) It increases the transcription of ER oxidoreductase 1 alpha (ERO1α), which then re-oxidizes PDI and generates ROS; (iii) It increases the transcription of the inositol 1,4,5-triphosphate receptor (IP3R), which then increases the calcium level in the cytoplasm; (iv) It activates the extrinsic cell death pathway via death receptor 5 (DR5) and caspase-8 mediated activation of truncated Bid (tBid), which then translocates to the mitochondria and promotes the release of cytochrome c; (v) It activates the intrinsic cell death pathway by directly decreasing the expression of pro-survival factors, Bcl-2 and Bcl-xL, and increasing the expression of pro-apoptotic factors, such as Bax, Bak, Bim, Puma, and Noxa; (vi) It activates caspase-8 via TRAIL-DR5 on the cytoplasmic membrane, which cleaves B cell receptor-associated protein 31 (BAP31) and forms p20. p20 then releases calcium from the ER into the cytoplasm, which is taken up by mitochondria and results in the further release of cytochrome c.

During their development, tumors rely heavily on the UPR pathway for cell survival, possibly due to the hypoxic environment and metabolic stress accompanying the rapidly increasing tumor mass. For example, PERK and ATF4 activate vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1/2 (HIF1/2) for angiogenesis [48]. The silencing of the XBP1 gene prevented tumor growth and metastasis of triple-negative breast cancer (TNBC) in vivo [50]. Analysis using TNBC cell lines demonstrated that the upregulation of XBP1 enhanced HIF1α expression. Nonetheless, when the URP system becomes overwhelmed, pro-apoptotic factors become dominant, leading to cell death.

2.3. The Effects of Inflammation and Microenvironment on Tumor Survival, Migration, and Immune Evasion

Tissue microenvironment often plays an important role in supporting tumor establishment, expansion, and metastasis. The tumor microenvironment is primarily comprised of infiltrated leukocytes, including tumor-associated macrophages (TAMs), dendritic cells, and myeloid-derived suppressor cells (MDSC) [51]. The crosstalk between the infiltrated cells and tumor cells could suppress the immune response and create a pro-survival environment for tumor cells.

Evasion of the attack by the immune system is essential during the development of cancers. This is accomplished through dynamic interactions between different cytokines and their receptors in the tumor microenvironment. Tumors actively secrete different cytokines that attract a variety of infiltrating cells, such as TAMs, dendritic cells, MSDCs, and immunosuppressive regulatory T cells, which in turn help tumors to evade the attack by the immune system ( Figure 4 A). Cytokines released from myeloid cells can also induce genomic instability in tumor cells by directly damaging DNA or epigenetically altering the expression of genes ( Figure 4 B).

The interplays between tumor cells and inflammatory cells during tumorigenesis. (A) The effect of tumor cells on inflammatory cells. Tumor cells secrete many cytokines to alter the microenvironment to promote tumor growth and invasion and to blunt the anti-tumorigenic immune response. (B) Inflammatory cells affect the genomic stability of tumor cells. AID: activation-induced cytidine deaminase; DNMT1: DNA methyltransferase 1. (C) Inflammatory cells enhance tumor cell proliferation and survival through autocrine and paracrine signaling. (D) Inflammatory cells promote tumor cell migration, invasion, and metastasis through cytokine and chemokine production. COX-2: cyclooxygenase 2; MMP: matrix metalloproteinase; E-cad: E-cadherin; EMT: epithelial-mesenchymal transition; sLex: sialyl Lewis X; CXCR: CXC chemokine receptor; BV: blood vessel.

The key inflammatory mediators for tumor proliferation and survival include NF-κB and signal transducer and activator of transcription 3 (STAT3) ( Figure 4 C) [52]. IL-6, secreted by the myeloid cells, activates STAT3, which then upregulates cyclins D1, D2, and B as well as MYC to promote tumor cell proliferation. STAT3 expressed by the tumor cells further enhances IL-6 secretion by the myeloid cells via increased expression of NF-κB in these inflammatory cells, thus creating a positive feedback loop. IL-22, produced by the CD11c+ lymphoid cells, is also able to activate STAT3 in epithelial cells. In parallel, TNF-α and IL-1 secretion from leukocytes can upregulate the expression of NF-κB in tumor cells [52,53,54]. NF-κB, in turn, upregulates the expression of IL-1α, IL-1R, and MYD88, which can further enhance the activity of NF-κB, thus creating a positive autocrine loop [52]. The expression of NF-κB can be directly activated in immune cells by the inflammatory cytokines, TNF-α and IL-1, and by TLR-MYD88 from tissue damage [53,54]. Downstream of IL-6 signaling, NF-κB has also been shown to induce epithelial-mesenchymal transition (EMT), which then promotes tumor cell migration [54]. In a prostate cancer model, the interaction between receptor activator of NF-κB (RANK), on the surface of cancer cells, and RANK ligand, on the infiltrating leukocytes, promoted metastasis through the activation of NF-κB pathway. This NF-κB/IL-6/STAT3 positive feedback loop is present in all phases of tumorigenesis.

Furthermore, the expression of STAT3 in tumor-associated leukocytes also plays a key role in immune modulation. STAT3 expression in inflammatory cells allows for immune evasion of tumors, while STAT3 deletion in macrophages and neutrophils enhances Th1-mediated response with increased production of IFNγ, TNF-α, and IL-1 [55]. STAT3 expression in myeloid cells can inhibit the maturation of dendritic cells by downregulating their IL-12 expression and suppresses the immune response by upregulating the expression of IL-23 in TAMs [53].

Collectively, the activation of NF-κB and STAT3 signaling transduction pathways in cancer cells, as well as in the inflammatory cells in the tumor microenvironment, provide a great advantage for tumor cell proliferation, survival, migration, and immune evasion ( Figure 4 C,D).

3. The Anti-Cancer Effects of CBD

3.1. Glioma

Glioma is the most common primary brain malignancy. The grade IV glioma, also called glioblastoma multiforme (GBM) or glioblastoma, is one of the most aggressive types of cancer. The prognosis of GBM is very poor with only 4–5% survival within five years. Current treatment modalities include surgery, followed by radiotherapy and chemotherapy with Temozolomide (TMZ) or Carmustine (BCNU). Unfortunately, most GBM tumors are resistant to these treatments.

Cannabinoids have been studied to a great extent in gliomas due to the urgent unmet medical needs. The Table S1 summarizes the published studies focusing on CBD’s effects on gliomas either alone or together with BCNU, TMZ, tamoxifen, cisplatin, γ-irradiation, ATM inhibitors, and Δ 9 -THC [56,57,58,59,60,61,62,63,64]. In these studies, many GBM cell lines were used with a majority using U87MG [56,57,58,60,61,63,65,66,67,68,69,70,71,72,73,74]. The anti-proliferative effects of CBD on GBMs are quite clear, but the average IC50 values of CBD differed among different cell lines: C6 (8.5 µM) [67], U87MG (12.75 ± 9.7 µM), U373 (21.6 ± 3.5 µM) [65,75], U251 (4.91 ± 6.1 µM) [57,60], SF126 (1.2 µM) [57], T98 (8.03 ± 4.0 µM) [58,59,60,70,73], MZC (33.2 µM) [69], and GL261(10.67 ± 0.58 µM) [59]. Variation among different publications may be due to procedural differences, including assays used to measure the viability and/or time of CBD exposure.

CBD, alone or with other agents, has been shown to successfully induce cell death, inhibit cell migration and invasion in vitro, decrease tumor size, vascularization, growth, and weight, and increase survival and induce tumor regression in vivo [58,59,62,65,68,70,71,74]. Regarding CBD’s anti-proliferative action on GBM, data show that apoptosis occurs independent of CB1, CB2, and TRPV1, but is dependent on TRPV2 [58,65,66,67,69,72]. Specifically, Ivanov et al. found that CBD, γ-irradiation, and ATM inhibitor KU60019 upregulate TNF/ TNFR1 and TRAIL/ TRAIL-R2 signaling along with DR5 within the extrinsic apoptotic pathway [61,64]. CBD also activates the JNK-AP1 and NF-κB pathways to induce cell death. Less emphasis has been placed on the role of autophagy or cell cycle arrest in CBD-mediated effects on glial cells [57,58,64,72,74].

Many downstream effects of CBD have been investigated. Multiple papers reported an increased level of oxidative stress in CBD, but not Δ 9 -THC, treated GBM cell lines [58,65,73,76]. Massi et al. found that the level of ROS increases in a time-dependent manner, with significance after only five hours, when U87MG cells were treated with 25 µM CBD [76]. At the same time, glutathione, an antioxidant, was significantly decreased after six hours of CBD treatment. In contrast, there is no pronounced ROS increase in CBD treated normal glial cells. Co-treatment of CBD and antioxidants, including N-acetyl cysteine (NAC) and α-tocopherol (i.e., vitamin E), attenuated CBD’s killing effects [58]. Taken together, studies in GBM cell lines suggest that CBD induces cell death most likely by upregulating ROS. Scott et al. found that CBD also increased the expression of heat shock proteins (HSPs), which was found to be associated with the increased production of ROS because NAC hindered the role of HSPs [73]. Interestingly, the use of HSP inhibitors together with CBD were shown to increase the cytotoxic effect and reduce CBD’s IC50 value significantly, from 11 ± 2.7 µM to 4.8 ± 1.9 µM in T98G cells. This suggests that HSP inhibitors may be used as an adjunctive treatment with CBD. Recently, Aparicio-Blanco et al. administered CBD in lipid nanocapsules (LNCs) to GBM in vitro in an attempt to provide a prolonged-release formula of CBD [75]. LNCs loaded with CBD were more effective at decreasing the IC50 values when they were smaller in size and exposed for longer periods.

In GBMs, CBD inhibits the PI3K/AKT survival pathway by downregulating the phosphorylation of AKT1/2 (pAKT) and p42/44 MAPKs without effecting the total AKT and p42/44 MAPK protein levels [57,59,61,70,72,73]. This pathway may also be responsible for CBD-mediated autophagy in glioma stem-like cells, since in those cells, PTEN is upregulated while AKT is downregulated [72]. PI3K pathway plays an important role in the expression of TRPV2, which is a potential target of CBD. In U251, Δ 9 -THC and CBD together, but not separately, downregulated p42/44 MAPKs [57]. Whereas Scott et al. revealed that alone, CBD treated T98G and U87MG cells, albeit at a higher concentration (20 µM), decreased pAKT and p42/44 MAPKs levels, and more so when combined with γ-irradiation [59]. CBD can also activate the pro-apoptotic MAP kinase pathway. Ivanov et al. found that CBD treatment together with γ-irradiation led to the upregulation of active JNK1/2 and p38 MAPK, especially in U87MG cells [61]. However, using U251 cells, Marcu et al. showed that Δ 9 -THC and CBD did not increase the activity of JNK1/2 or p38 MAPK [57]. The discrepancy could be due to the genetic difference among different GBM cell lines.

Massi et al. explored how CBD modulates 5-lipoxygenase (5-LOX), COX-2, and the endocannabinoid system in GBMs [68,73,76]. They found that 5-LOX, but not COX-2, was decreased by CBD in vivo. CBD treatment also resulted in increased expression of fatty acid amide hydrolase (FAAH), which reduces the level of AEA, suggesting that CBD may inhibit the production of inflammatory mediators by indirectly attenuating the endocannabinoid system in GBMs.

In addition to γ-irradiation, CBD has also been tested with alkylating agents, especially TMZ, proving together to have synergistic anti-proliferative effects on glioma cells [60,62,63,74]. Kosgodage et al. found that CBD-treated cells, alone and with TMZ, increased extracellular vesicles (EV) containing anti-oncogenic miR-126 [63]. There were also reduced levels of pro-oncogenic miR-21 and prohibitin, which are responsible for chemo-resistant functions and mitochondria protective properties.

In pre-clinical GBM mouse models, oral administration of a Sativex-like combination of Δ 9 -THC and CBD, at a 1:1 ratio with TMZ, decreased tumor growth and increased survival [62,74]. These findings have led to two phase I/II clinical trials [77,78]. Preliminary results are only available for one study and are promising ( > NCT01812603) [79]. Patients with GBM were either treated with the Sativex, CBD:Δ 9 -THC (1:1), oro-mucosal spray with dose-intense TMZ, or placebo, and the first part of the study showed no Grade 3 or 4 toxicities. In the second part of this study, the same drug combination increased median survival compared to a placebo group with increased one-year survival of 83% and 56%, respectively. The most common adverse effects reported of the treatment were dizziness and nausea. Resistance to TMZ treatment may be reduced by using CBD: Δ 9 -THC combinations. When the full report is published, we are hopeful that the authors will discuss the safety and efficacy in more detail and help to determine which adverse effects can be attributed to Sativex versus TMZ.

There are also a few case studies that described the use of CBD in patients with high-grade gliomas [80,81]. Two patients were treated with procarbazine, lomustine, and vincristine along with CBD (one patient at 100–200 mg/day orally and the other at 300–450 mg/day orally) for about two years [80]. Both patients did not have any disease progression for two years after treatment. Adverse effects of the treatment included rash, moderate nausea, vomiting, and fatigue, without any lymphopenia, thrombocytopenia, hepatic toxicity, or neurotoxicity. In a case series describing nine patients with grade IV GBM, mean survival with the combination of surgery, radio- and chemo-therapy, and CBD (200–400 mg/day) was prolonged to 22.3 months, and two patients had no signs of disease progression for three or more years [81].

Taken together, the published results indicate that CBD alone, or in combination with Δ 9 -THC, TMZ, or γ-irradiation, show great promise in the treatment of glioma. Furthermore, the adverse effects of CBD alone, or together with Δ 9 -THC, appear to be relatively benign.

3.2. Breast Cancer

Breast cancer is the number one leading cause of new cancer cases and the second leading cause of cancer deaths of women in the United States [82]. CBD’s effects on breast cancer have been studied since 2006; research in the field has undergone recent expansion (Table S2). Various breast cancer cell lines have been used to demonstrate a dose-dependent response to CBD, including estrogen-receptor (ER)-positive cells (MCF-7, ZR-75-1, T47D), ER-negative cells (MDA-MB-231, MDA-MB-468, and SK-BR3), and triple-negative breast cancer (TNBC) cells (SUM159, 4T1up, MVT-1, and SCP2) [67,83,84,85,86,87,88]. As low as 1 to 5 µM of CBD induced significant cell death in MDA-MB-231 after 24 h [89]. CBD’s IC50 values for most cell lines are consistently low, indicating that breast cancer cell lines are generally sensitive to CBD’s anti-proliferative effects without a significant effect on non-transformed breast epithelial cells [87].

CBD exerts its anti-proliferative effects on breast cancer cells through a variety of mechanisms, including apoptosis, autophagy, and cell cycle arrest [67,83,87]. Ligresti et al. reported that CBD-treated MDA-MB-231 cells induced an apoptotic effect involving caspase-3, whereas CBD exerted its effects on MCF-7 through cell cycle arrest at the G1/S checkpoint [67]. That being said, cell cycle arrest at the G1/S checkpoint has been more recently demonstrated in MDA-MB-231 and 4T1 cells after CBD treatment [90]. While the activation of CB2 and TRPV1 receptors were seen in MDA-MB-231 cells, the effect was partial. More recent studies have found the anti-proliferative effects of CBD on breast cancer cells to be independent of the endocannabinoid receptors [87]. CBD has been consistently shown to generate ROS, which in turn inhibit proliferation and induce cell death [63,67,87,88,89]. CBD exerts its pro-apoptotic effects by downregulating mTOR, AKT, 4EBP1, and cyclin D while upregulating the expression of PPARγ and its nuclear localization [83,87]. Shrivastava et al. showed that inhibition of the AKT/mTOR signaling pathway and induction of ER stress also induced autophagy alongside apoptosis [87]. At increased CBD concentrations, or when autophagy was inhibited, the levels of apoptosis increased. They further showed that CBD may coordinate apoptosis and autophagy through the translocation and cleavage of Beclin-1.

CBD has also been shown to inhibit migration, invasion, and metastasis in aggressive breast cancer in vivo and in vitro [67,84,88,90]. McAllister et al. observed downregulated Id-1 protein by ERK and ROS in CBD-treated MDA-MB-231 and MDA-MB-436 tumors. This downregulation correlated with a decrease in tumor invasion and metastases [86,90]. Id-1 expression was also found to be downregulated in lung metastatic foci. Consistent with these observations, CBD failed to inhibit lung metastasis in Id-1 overexpressed breast cancer cells [88]. Interestingly, this same study showed that at a lower concentration (1.5 µM), which produced ROS and inhibited the expression of Id-1 in MDA-MB-231 cells, CBD did not induce autophagy or apoptosis [88]. More recently, CBD was shown to inhibit the proliferative, migratory, and invasive nature of TNBC cells by suppressing the activation of the EGF/ EGFR pathway and its downstream targets (AKT and NF-κB) [84]. MMP, phalloidin, and actin stress fibers are important in tumor invasion and were also suppressed by CBD. These results, as they pertain to EGF/EGFR pathway and the MMP, phalloidin, and actin stress fibers, were also confirmed in vivo. Primary tumor size has been shown to decrease along with the number of lung metastatic foci, volume, and vascularization in CBD-treated mice [84,90]. Intriguingly, when CBD was administered three times a week, rather than daily as was done by McAllister et al., the number of metastases were reduced and mice survived longer, but the primary tumor was not reduced [88,90]. The decreased angiogenesis and invasion were found to be due to a change in the tumor microenvironment, for example, a marked decrease in CCL3, GM-CSF, and MIP-2, which resulted in the inhibition of TAMs recruitment ( Figure 4 A) [84]. Finally, another study described a synthetic cannabinoid analog, O-1663, which was shown to be more potent than both CBD and Δ 9 -THC, and similarly induced cell death and autophagy [88]. O-1663 also inhibited breast cancer aggressiveness in vitro and in vivo. It significantly increased the survival in advanced breast cancer metastasis, inhibited the formation of metastatic foci ≥2 mm, and induced regression of established metastatic foci, all with no pronounced toxicity. Altogether, the evidence suggests that there are multiple mechanisms by which CBD impedes tumor migration.

Kosgodage et al. showed that breast cancer cells treated with CBD had increased sensitization to cisplatin. CBD significantly decreased the release of exosomes and microvesicles (EMV) (at 100–200 nm), which typically aid the spread of tumors and cause chemo-resistance [89]. However, in these same MDA-MB-231 cells, there was an increase in the release of the larger EMVs (201–500 nm). These cells displayed a concentration-dependent increase in ROS, proton leakage, mitochondrial respiration, and ATP levels. The authors attributed these effects to either a higher sensitivity or a sign of pseudo-apoptotic responses occurring, where the apoptotic factors such as ROS are still at a lower level resulting in the conversion of apoptosomes into EMVs. CBD inhibited paclitaxel-induced neurotoxicity through a 5-HT1A receptor system without conditioned reward or cognitive impairment [85]. It also decreased the viability of both 4T1 and MDA-MB-231 cells. Thus, CBD may be a viable adjunctive treatment for breast cancers as it can sensitize cells, allowing for potentially lower doses of such toxic chemicals to be prescribed.

Taken together, CBD has been consistently shown to be efficacious in many breast cancer cells and mouse models when it comes to its anti-proliferative and pro-apoptotic effects, while the mechanisms of these effects may vary. At this point, there is an urgent need for clinical trials looking at the anti-tumor effect of CBD for breast cancers, as this seems to be the next logical step in the progression of developing CBD as a treatment alternative for breast cancers.

3.3. Lung Cancer

Based on epidemiological studies by the American Cancer Society, lung cancer is the second most common cancer in both males and females [82]. Lung cancers are classified as small cell lung cancer (SCLC, 13%) and non-small cell lung cancers (NSCLC, 84%), which can be further subdivided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

Ramer and colleagues have published many studies on the effects of CBD on lung cancers (Table S3) [91,92,93,94]. They consistently used the WST-1 assay to assess the viability of lung cancers. CBD decreased the viability of two NSCLC cell lines, A549 (a lung adenocarcinoma cell line) and H460 (a large cell lung carcinoma cell line), with IC50 values of 3.47 µM and 2.80 µM, respectively [94]. There was a 29% and 63% reduction in A549 invasion after incubation with 0.001 µM or 0.1 µM CBD, respectively, for 72 h [92]. There was no significant cell death detected in A549 cells after treatment with 0.001 µM or 0.1 µM CBD. Various lung cancer cell lines (e.g., A549, H358, and H460) have been shown to express CB1, CB2, and TRPV1, which the anti-invasive function of CBD partly relies on [91,92,93]. CBD also significantly reduced tumor size and lung metastatic nodules (from an average of 6 nodules to only 1 nodule) in an A549 xenograft tumor model [92,93].

One mechanism of the pro-apoptotic effect of CBD is through the activation of COX-2, a pathway for endocannabinoid degradation, and PPAR-γ [94]. CBD treatment, at 3 µM in A549, H460, and primary lung tumor cells from a patient with brain metastasis, resulted in the upregulation of COX-2 and PPAR-γ both mRNA and protein. These observations were also confirmed in vivo. COX-2-derived products (PGE2, PGD2, and 15d-PGJ2) were also elevated in CBD-treated lung cancer cells. By suppressing COX-2 and PPAR-γ activity with antagonists or siRNA, CBD’s pro-apoptotic and cytotoxic effects were severely attenuated. Consistently, in a lung tumor mouse model, PPAR-γ inhibition by GW9662 reversed the tumor-suppressive effects of CBD.

While Ramer et al. discussed plasminogen activator inhibitor-1’s (PAI-1) pro- vs. anti-tumorigenic actions, they provided evidence supporting the former [92]. At 1 µM CBD, there was a decrease in PAI-1 mRNA and protein in A549, H358, and H460. This was confirmed in vivo using the A549 mouse model with 5 mg/kg CBD three times a week. In vitro, CBD’s anti-invasive property was reduced by siRNA knockdown of PAI-1 and was increased with the treatment of a recombinant PAI-1. The CBD-mediated decrease in PAI-1 is due, in part, to the activation of CB1, CB2, and TRPV1, as their antagonists reversed the effect. Therefore, CBD works as an agonist of CB1, CB2, and TRPV1 in lung cancers.

Tissue inhibitor of MMPs (TIMPs) were evaluated and are related to the anti-invasive effect of CBD and were found to be induced by CBD in a time- and concentration-dependent manner [93]. CBD-mediated upregulation of TIMP-1 was attributed to the activation of CB1, CB2, and TRPV1. CBD also activated p38 MAPK and p42/44 MAPK, two downstream targets of TRPV1. To connect CB1, CB2, and TRPV1 to the activation of MAPK and TIMP-1, Ramer et al. investigated the expression and function of intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein involved in tumor metastasis [91] ( Figure 5 A). Time- and concentration-dependent increase of ICAM-1 was observed in CBD-treated A549, H358, H460, and cells from a patient with brain metastatic NSCLC. An increase in the expression of TIMP-1 mRNA was also observed, but it occurred after an increase of ICAM-1 mRNA. The expression of ICAM-1 was dependent on the activation of p42/44 MAPK and p38 MAPK. In the in vivo A549 model displaying CBD’s anti-invasive properties, both ICAM-1 and TIMP-1 were also upregulated. Inactivation of ICAM-1 using a neutralizing antibody and siRNA led to a decrease in TIMP-1 activation as well as a reduction in CBD’s anti-invasive properties. These data suggest that the MAPKs activate ICAM-1, which then stimulates the function of TIMP-1 that, in turn, suppresses tumor invasion.

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CBD’s effects on cancer cells and infiltrating immune cells. (A) Through its interactions with the CB1, CB2, and TRPV1 receptors, CBD induces cell cycle arrest and apoptosis in cancer cells. (B) CBD also binds the CB1 and CB2 receptors on the infiltrating inflammatory cells and disrupts the pro-tumorigenic cytokine production, thus leading to ineffective immunosuppression and promoting tumor cell death. ROS production by phagocytic cells disrupts the ER and mitochondrial homeostasis in tumor cells leading to apoptosis. UPR: unfolded protein response.

In a separate study, Haustein et al. investigated CBD-induced ICAM-1 expression on lymphokine-activated kill (LAK) cell-mediated cytotoxicity [95]. Treatment with 3 µM CBD induced ICAM-1 expression and LAK cell-mediated tumor cell lysis in A549 and H460, along with metastatic cells from a patient with NSCLC. The increased susceptibility to adhesion and lysis by LAK in CBD-treated cells was reversed using a neutralizing ICAM-1 antibody. This cell lysis effect was reversed with the usage of ICAM-1 siRNA, along with CB1, CB2, and TRPV1 antagonists. Lymphocyte function association antigen (LFA-1) reversed CBD-induced killing effects on LAK cells, suggesting that it works as a counter-receptor to ICAM-1 [95]. Finally, CBD did not induce LAK cell-mediated lysis and upregulation of ICAM-1 of non-tumor bronchial epithelial cells, suggesting this effect is specific to cancer cells.

Taken together, these studies suggest that through CB1, CB2, and TRPV1 receptors, CBD activates p38 MAPK and p42/44 MAPK, which first induce ICAM-1 and then TIMP-1. The upregulation of ICAM-1 and TIMP-1 then attenuates the invasion of lung cancers ( Figure 5 A).

At present, there are no published results on a clinical trial using CBD to treat lung cancer patients. However, in a recent case report, an 81-year-old male patient attempted to self-treat his lung adenocarcinoma using CBD oil [96]. When first diagnosed with a mass 2.5 × 2.5 cm in size and multiple mediastinal masses, the patient was denied chemotherapy and radiation therapy given his age and the toxicity profile of these treatments. However, a year later, computed tomography (CT) scan showed that the tumor and mediastinal lymph nodes began to regress. During that period, the primary factor that was changed was that he began taking 2% CBD oil. Adverse effects included slight nausea and sickening taste.

3.4. Colorectal Cancer

In the US, colorectal cancer (CRC) is the third leading cause of cancer deaths in both males and females [82]. Studies using two CRC cell lines, Caco-2 and DLD-1, as well as healthy and cancerous tissues from nine CRC patients, suggest that endocannabinoid production is significantly increased in precancerous adenomatous polyps and, to a lesser extent, cancerous colon tissue [97]. Normal human colorectal tissue does express both CB1 and CB2, along with AEA, 2-AG, and endocannabinoid-metabolizing enzymes such as FAAH. Transformed adenomatous polyps have increased levels of 2-AG compared to normal colorectal tissues. While DLD-1 cells express both CB1 and CB2, Caco-2 cells only express CB1. Depending on the stage of the cancer, endocannabinoids can either inhibit or promote the growth of CRC. Thus, based on the stage of the cancer, both activators and inhibitors of the endocannabinoid system may be useful in combating CRC.

CBD’s effects on CRC are summarized in Table S4. The dose-dependent killing of CRC cells by CBD has been demonstrated by many studies, however, the IC50 values of SW480 have been reported to be as low as 5.95 µM and as high as 16.5 µM over a 48 h period [98,99,100]. This dose-dependent killing response is specific to CRC cells and not normal human colorectal cells [101]. The IC50 value for CaCo-2 was reported as 7.5 ± 1.3 µM [67]. Under the physiologic oxygen conditions in the colon, estimated around 5%, Caco-2 were even more sensitive to CBD, showing a decline in proliferation at 0.5 µM compared to 1 µM under atmospheric oxygen (~20%) [102]. The same study found that under physiologic oxygen conditions, the anti-proliferative effects of CBD are likely due to its ability to induce mitochondrial ROS. Apoptosis has been described as the main pathway of cell death by CBD in CRC [98,101,103].

Sreevalsan et al. used SW480 cells with 15 µM of CBD to show that the apoptosis was phosphatase- and endocannabinoid-dependent [98]. After 24 h, CBD induced the expression of various dual-specificity phosphatases and protein tyrosine phosphatases, including DUSP1, DUSP10, serum ACPP, cellular ACPP, and PTPN6. Consistent with the hypothesis, apoptosis was reduced with the use of a phosphatase inhibitor, sodium orthovanadate (SOV). Knocking down CB1 and CB2 also inhibited apoptosis. Together, these studies indicate that the apoptotic effect of CBD in CRC is through the endocannabinoid system and the activation of its downstream targets, including various phosphatases.

CBD has been shown to induce Noxa-mediated apoptosis through the generation of ROS and excessive ER stress [101]. In HCT116 and DLD-1 cells, CBD treatment induced ROS overproduction, especially mitochondrial superoxide anion, and this was linked to Noxa activation. Jeong et al. also found that Noxa-activated apoptosis was dependent on excessive ER stress from ATF3 and ATF4 [101]. These proteins bind the Noxa promoter and stimulate its expression. Similarly, in vivo, CBD-treated CRC tumors also resulted in a significant decrease in tumor size and induction of apoptosis by Noxa.

Using HCT115 and Caco-2 cells, Aviello et al. found that 10 µM of CBD exerts anti-proliferative effects through multiple mechanisms [104]. CBD may act through indirect activation of the receptors by increasing endocannabinoids, specifically 2-AG, in CRC cell lines. In vivo, CBD at 1 mg/kg significantly reduced azoxymethane-induced aberrant crypt foci, polyps, tumors, and the percentage of mice bearing polyps. CBD’s antitumor mechanism was determined to be through the downregulation of the PI3K/AKT pathway and the upregulation of Caspase-3.

A few studies also investigated CBD as an adjunctive to chemotherapy for CRC [101,103]. CRC is often treated surgically in conjunction with the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). Seeking to overcome the potential resistance to FOLFOX, Jeong et al. treated oxaliplatin resistant DLD-1 and colo205 cells with oxaliplatin and CBD (4 µM) and found that CBD was able to enhance oxaliplatin-mediated autophagy through decreased phosphorylation of NOS3, which is involved in the production of nitric oxide (NO) and plays a role in oxaliplatin resistance [100]. The combination of oxaliplatin and CBD caused mitochondrial dysfunction (decreased oxygen consumption rate, mitochondrial membrane potential, mitochondrial complex I activity, and the number of mitochondria) through reduced SOD2 expression. These results were confirmed in vivo as well.

An alternative targeted therapy for CRC cancer, TNF-related apoptosis-inducing ligand (TRAIL), has also displayed resistance that can be overcome with the addition of CBD (4 µM) in HCT116, HT29, and DLD-1 cells [103]. CBD and TRAIL increased apoptosis through the activation of ER stress-related genes, including PERK, CHOP, and DR5. In vivo, TRAIL with CBD showed a significant decrease in tumor growth and an increased number of apoptotic cells. Altogether, these FOLFOX and TRAIL therapy studies suggest that CBD may be considered as a therapeutic option for CRC or, perhaps, as an adjunctive treatment to work synergistically with conventional chemotherapies. Currently, there are no clinical trials related to CBD in CRC, however, these findings related to the synergistic effects of CBD with chemotherapies are very promising and make a good case for a clinical trial in the future.

3.5. Leukemia/Lymphoma

Our understanding of CBD’s effects on leukemia and lymphoma has expanded in recent years (Table S5). EL-4 and Jurkat cell lines are the commonly used models for lymphoma and leukemia, respectively. CBD induced a dose- and time-dependent killing effect on these leukemia and lymphoma cell lines, whereas peripheral blood monomolecular cells were more resistant to CBD [105,106,107,108,109].

McKallip et al. [106] found that in both EL-4 and Jurkat cells, CBD’s anti-proliferative effects were mediated through CB2, but independent of CB1 and TRPV1 [106]. However in a separate study Olivas-Aguirre et al. showed CBD’s effects to be independent of the endocannabinoid receptors and plasma membrane Ca 2+ channels in Jurkat cells [110]. These conflicting results need to be resolved by future studies. Despite this, the majority of research on leukemia/lymphomas confirmed apoptosis as the mechanism by which CBD-mediated cell death occurs, either alone or in combination with other treatment modalities, including γ-irradiation, Δ 9 -THC, vincristine, and cytarbine [105,106,107,110]. One study also demonstrated that CBD decreased tumor burden and induced apoptosis in vivo [106]. Kalenderoglou et al. found that CBD can induce cell cycle arrest in Jurkat cells, with increased cells in G1 phase [108]. CBD treatment also resulted in changes to cell morphology, including decreased size of cells, extensive vacuolation, swollen mitochondria, disassembled ER and Golgi, and plasma membrane blebbing [108,110].

Similar to the results of other cancers as discussed above, CBD also induced ROS in leukemia and lymphoma [106,110,111]. Treating Jurkat and MOLT-4, another leukemia cell line, with ≥2.5 µM CBD for 24 h induced increased ROS levels [106]. Treating cells together with ROS scavengers, α-tocopherol and NAC, reduced CBD’s killing effects. CBD exposure also increased NOX4 and p22 phox while inhibiting NOX4 and p22 phox decreased ROS levels and inhibited CBD-induced cell toxicity. Consistent with these observations, ROS levels were significantly increased after only two hours of CBD treatment in EL-4 cells, with a concomitant decrease in cellular thiols [111].

Kalenderoglou et al. explored CBD’s effects on the mTOR pathway in Jurkat cells [108]. They found that CBD reduced the phosphorylation of AKT and ribosomal protein S6. They also tested CBD’s effects with different nutrient and oxygen conditions and found that CBD’s anti-proliferative effects alone or together with doxorubicin were greater with 1% serum than 5% serum. Olivas-Aguirre et al. found that when Jurkat cells were treated with lower concentrations of CBD, proliferation still occurred (at 1 µM CBD) and autophagy was increased at 10 µM CBD [110]. However, at higher concentrations (30 µM), the intrinsic apoptotic pathway was activated, resulting in cytochrome c release and Ca 2+ overload within the mitochondria. In Burkitt lymphoma cell lines, Jiyoye and Mutu I, AF1q stimulated cell proliferation and reduced ICAM-1 expression, through which cells became resistant to chemotherapies [104]. After exposure to CBD for 24 h, the chemo-resistant effect was dramatically attenuated.

3.6. Prostate Cancer

Prostate cancer is the most common cancer and the second most common cause of cancer-related deaths in men [82]. The detailed summary of studies describing CBD’s effects on prostate cancer can be found in Table S6. The prostate cancer cell lines used in those studies can be divided into androgen receptor (AR)-positive (LNCaP and 22RV1) and AR-negative (DU-145 and PC-3). CBD can inhibit the expression of the androgen receptor in AR-positive cell lines [112]. Regarding the endocannabinoid receptors, depending on the specific cancer cell type, either CB1, or CB2, or both, are upregulated in prostate cancer cells relative to normal prostate cells [112,113]. Specifically, 22RV1 only expresses CB1 while DU-145 only expresses CB2. Though CB1 and CB2 can be found in both LNCaP and PC-3, their levels are much more prominent in PC-3. TRPV1 is expressed in all four prostate cancer cell lines, with the highest expression found in DU-145 cells.

CBD induced anti-proliferative effects and apoptosis-mediated cell death (via the intrinsic pathway) in prostate cancer cells, which may be dependent on CB2, but not CB1, and the transient receptor potential cation channel subfamily M member 8 (TRPM8) receptor in LNCaP cells [112,113]. Additionally, treatment with CBD was shown to downregulate the expression prostate-specific antigen (PSA), vascular endothelial growth factor (VEGF), and pro-inflammatory cytokines [113]. CBD treatment resulted in cell cycle arrest at G0/G1 transition in LNCaP and PC3 cells and G1/S transition in DU-145 cells.

Similar to the CRCs, Sreevalsan et al. found that dual-specificity phosphatases and protein tyrosine phosphatases were also induced by CBD in LNCaP cells [98]. Inhibition of the phosphatases with the phosphatase inhibitor, SOV, decreased PARP cleavage. Additionally, CBD enhanced the phosphorylation of p38 MAPK. Most recently, Kosgodage et al. found that in PC3, CBD treatment (1 µM and 5 µM) reduced the release of EMV [89,114]. CBD was also shown to reduce mitochondrial-associated proteins, prohibitin, and STAT3, which may account for the decrease of EMV.

At this point, only one study testing CBD’s effectiveness on prostate cancer has been conducted in vivo. More quality studies using mouse models are required before moving to the clinical trial phase.

3.7. Other Cancer Types:

The effects of CBD on a variety of other cancers have also been reported, however to a lesser degree (Table S7). Cervical cancer cell lines treated with CBD had time- and concentration-dependent killing effects that were shown to be mediated by apoptosis and independent of cell cycle arrest [93,115]. Treatment with CBD resulted in the upregulation of p53 and Bax, a pro-apoptotic protein, and downregulation of RBBP6 and Bcl-2, two anti-apoptotic proteins, in SiHa, HeLa, and ME-180 cells [115]. CBD also decreased the invasion of HeLa and C33A, which was dependent on CB1, CB2, and TRPV1. Ramer et al. also found this anti-invasive property of CBD to be associated with the upregulation of p38 MAPK and p42/44 MAPK, along with their downstream target, TIMP-1, which is similar to lung cancers as discussed above ( Figure 5 A).

CBD (1 µM and 5 µM) also decreased the cell viability of a hepatocellular carcinoma cell line, Hep G2, in a dose-dependent manner after 24 h [89]. Similar to the breast and prostate cell lines, MDA-MB-231 and PC3, respectively, CBD-treated Hep G2 cells reduced the release of EMV and the expression of CD63, prohibitin, and STAT3. Additionally, treating Hep G2 cells with CBD sensitized them to cisplatin. Neumann-Raizel et al. used the mouse hepatocellular carcinoma cell line, BNL1 ME, which expresses functional TRPV2 channels, to demonstrate the effects of CBD in conjunction with doxorubicin [116]. CBD (10 µM) was shown to activate TRPV2 and inhibit the P-glycoprotein ATPase transporter, allowing for increased entry and accumulation of doxorubicin into the cell since it is transported across the cytoplasmic membrane through TRPV2 and pumped out of the cell using the P-glycoprotein ATPase transporter. These effects were likely responsible for CBD’s ability to decrease the dose of doxorubicin required to reduce cell viability and proliferation.

Regarding thyroid cancers, CBD induced an anti-proliferative effect in KiMol through the activation of apoptosis and cell cycle arrest [67]. KiMol was shown to contain increased levels of CB1, CB2, and TRPV1, but inhibitors of CB1, CB2, and TRPV1 only slightly decreased the anti-proliferative effects of CBD. CBD (5 mg/kg twice per week) produced anti-tumor effects in a mouse thyroid tumor model as well.

Taha et al. studied patients with stage IV non-small cell lung cancer, clear cell renal cell carcinoma, and advanced melanoma treated with nivolumab immunotherapy (anti-PD-1 agents) and patients who had additionally used cannabis, including CBD and Δ 9 -THC [117]. They showed a decreased response rate to treatment in groups using cannabis with nivolumab, whereas patients not using cannabis were 3.17 times more likely to respond to treatment with nivolumab. However, cannabis use resulted in no significant difference in overall survival and progression-free survival. This group suggested that there may be a possible negative interaction between cannabis and immunotherapy.

CBD decreased cell proliferation and colony formation in a concentration-dependent manner in gastric cancer cells without affecting normal gastric cells [67,118,119]. The gastric adenocarcinoma cell line, AGS, has abundant expression of TRPV1 without the detection of CB1 or CB2 [67]. Zhang et al. found that CBD induced cell cycle arrest by inhibiting the expression of CDK2 and cyclin E in SGC-7901, another gastric cancer cell line [119]. In addition, CBD increased the expression of ATM and p21, while decreasing that of p53. CBD’s anti-proliferative effects in SGC-7901 were also attributed to mitochondrial-dependent apoptosis, as it increased the activity of Caspase-3 and Caspase-9, the release of cytochrome c, and the expression of Apaf-1, Bad, and Bax proteins and decreased the expression of Bcl-2. CBD-induced cell cycle arrest and apoptosis were associated with increased ROS levels. In multiple gastric cancer cell lines, Jeong et al. showed that CBD caused apoptosis by inducing ER stress, which then upregulated the second mitochondria-derived activator of caspase (Smac) [118]. Smac upregulation resulted in downregulation of X-linked inhibitor of apoptosis (XIAP) through ubiquitination/proteasome activation. CBD was also shown to induce mitochondrial dysfunction ( Figure 5 A), as shown by CBD-driven decreases in oxygen consumption rate, ATP production, mitochondrial membrane potential, and NADH dehydrogenase ubiquinone 1α sub-complex subunit 9. In vivo, mice injected with MKN45, another gastric cancer cell line, showed slower tumor growth and smaller tumor size with CBD treatment (20 mg/kg) three times a week. Like the in vitro studies, CBD promoted apoptosis and decreased the expression of XIAP in the tumors.

Melanoma cancer cell lines (B16 and A375) express the endocannabinoid receptors, CB1, and CB2 [120]. Previous studies have also shown that activation of these receptors with Δ 9 -THC decreased melanoma growth, proliferation, angiogenesis, and metastasis in vivo [120]. While Δ 9 -THC looks promising as a treatment modality of melanoma, there has been little research on the effects of CBD on melanoma. A recent study by Simmerman et al. tested CBD in a murine melanoma model (B16F10) [121]. They set up three groups of mice: control (ethanol- and PBS-treated), cisplatin-treated (5 mg/kg intraperitoneal once per week), and CBD-treated (5 mg/kg intraperitoneal twice a week). Survival time was significantly increased, and tumor size was significantly decreased in CBD-treated mice compared to control mice, but to a lesser effect when compared to that of cisplatin-treated mice. Quality of life was subjectively described, and CBD-treated mice were found to have a better quality of life, improved movement, and less hostile interaction/fighting compared to both controls and cisplatin-treated mice. This study did not include a group of CBD and cisplatin combination treatment. More research is required to understand the effects of CBD on human melanoma cells.

Pancreatic cancers, especially pancreatic ductal adenocarcinoma (PDAC), have seen few improvements in treatment and survival. Ferro et al. used PDAC cancer cell lines, including ASPC1, HPAFII, BXPC3, and PANC1, as well as the KRAS Wt/G12D /TP53 WT/R172H /Pdx1-Cre +/+ (KPC) mice as models of PDAC to demonstrate GPR55 accumulating in PDAC tissue, and that its disruption resulted in improved survival and reduced proliferation both in vivo and in vitro [122]. This mainly occurred via cell cycle arrest at the G1/S transition by reducing the expression of cyclins, without increasing apoptosis. Additionally, they found downstream MAPK/ERK signaling to be inhibited in cells depleted of GPR55. In vivo, treatment of KPC mice with CBD (100 mg/kg) increased survival similar to gemcitabine (GEM) (100 mg/kg), and when CBD and GEM were used together survival was increased about three-fold compared to the control. With this combination, cell proliferation was also reduced. CBD was also able to counteract the increased ERK activation by GEM, a proposed mechanism of acquired GEM resistance.

4. Summary and Conclusions

As evidenced by the large volume of literature reviewed above, CBD has demonstrated robust anti-proliferative and pro-apoptotic effects on a wide variety of cancer types both in cultured cancer cell lines and in mouse tumor models. In comparison, CBD generally has milder effects on normal cells from the same tissue/organ. The anti-tumor mechanisms vary based on tumor types, ranging from cell cycle arrest to autophagy, to cell death, or in combination. In addition, CBD can also inhibit tumor migration, invasion, and neo-vascularization ( Figure 5 A), suggesting that CBD not only acts on tumor cells but can also affect the tumor microenvironment, for example by modulating infiltrating mesenchymal cells and immune cells. The dependency of CBD on the endocannabinoid receptors, CB1 and CB2, or the TRPV family of calcium channels, also varies, suggesting that CBD may have multiple cellular targets and/or different cellular targets in different tumors ( Table 1 ). Mechanistically, CBD seems to disrupt the cellular redox homeostasis and induce a drastic increase of ROS and ER stress, which could then exert the cell cycle arrest, autophagy, and cell death effects ( Figure 5 A). For future studies, it is crucial to elucidate the interplays among different signaling transduction pathways, such as ROS, ER stress, and inflammation, in order to better understand how CBD treatment disrupts cellular homeostasis in both tumor cells as well as infiltrating cells, leading to cancer cell death and inhibition of tumor migration, invasion, metastasis, and angiogenesis. The final step of developing CBD as an oncology drug is through extensive and well-designed clinical trials, which are urgently needed.

Cannabis and Cannabinoids (PDQ®)–Health Professional Version

This cancer information summary provides an overview of the use of Cannabis and its components as a treatment for people with cancer-related symptoms caused by the disease itself or its treatment.

This summary contains the following key information:

  • Cannabis has been used for medicinal purposes for thousands of years.
  • By federal law, the possession of Cannabis is illegal in the United States, except within approved research settings; however, a growing number of states, territories, and the District of Columbia have enacted laws to legalize its medical and/or recreational use.
  • The U.S. Food and Drug Administration has not approved Cannabis as a treatment for cancer or any other medical condition. components of Cannabis, called cannabinoids, activate specific receptors throughout the body to produce pharmacological effects, particularly in the central nervous system and the immune system.
  • Commercially available cannabinoids, such as dronabinol and nabilone, are approved drugs for the treatment of cancer-related side effects.
  • Cannabinoids may have benefits in the treatment of cancer-related side effects.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

Cannabis, also known as marijuana, originated in Central Asia but is grown worldwide today. In the United States, it is a controlled substance and is classified as a Schedule I agent (a drug with a high potential for abuse, and no currently accepted medical use). The Cannabis plant produces a resin containing 21-carbon terpenophenolic compounds called cannabinoids, in addition to other compounds found in plants, such as terpenes and flavonoids. The highest concentration of cannabinoids is found in the female flowers of the plant.[1] Delta-9-tetrahydrocannabinol (THC) is the main psychoactive cannabinoid, but over 100 other cannabinoids have been reported to be present in the plant. Cannabidiol (CBD) does not produce the characteristic altered consciousness associated with Cannabis but is felt to have potential therapeutic effectiveness and has recently been approved in the form of the pharmaceutical Epidiolex for the treatment of refractory seizure disorders in children. Other cannabinoids that are being investigated for potential medical benefits include cannabinol (CBN), cannabigerol (CBG), and tetrahydrocannabivarin (THCV).

Clinical trials conducted on medicinal Cannabis are limited. The U.S. Food and Drug Administration (FDA) has not approved the use of Cannabis as a treatment for any medical condition, although both isolated THC and CBD pharmaceuticals are licensed and approved. To conduct clinical drug research with botanical Cannabis in the United States, researchers must file an Investigational New Drug (IND) application with the FDA, obtain a Schedule I license from the U.S. Drug Enforcement Administration, and obtain approval from the National Institute on Drug Abuse.

In the 2018 United States Farm Bill, the term hemp is used to describe cultivars of the Cannabis species that contain less than 0.3% THC. Hemp oil or CBD oil are products manufactured from extracts of industrial hemp (i.e., low-THC cannabis cultivars), whereas hemp seed oil is an edible fatty oil that is essentially cannabinoid-free (see Table 1). Some products contain other botanical extracts and/or over-the-counter analgesics, and are readily available as oral and topical tinctures or other formulations often advertised for pain management and other purposes. Hemp products containing less than 0.3% of delta-9-THC are not scheduled drugs and could be considered as Farm Bill compliant. Hemp is not a controlled substance; however, CBD is a controlled substance.

Table 1. Medicinal Cannabis Products—Guide to Terminology

Name/Material Constituents/Composition
CBD = cannabidiol; THC = tetrahydrocannabinol.
Cannabis species, including C. sativa Cannabinoids; also terpenoids and flavonoids
• Hemp (aka industrial hemp) Low Δ 9 -THC (<0.3%); high CBD
• Marijuana/marihuana High Δ 9 -THC (>0.3%); low CBD
Nabiximols (trade name: Sativex) Mixture of ethanol extracts of Cannabis species; contains Δ 9 -THC and CBD in a 1:1 ratio
Hemp oil/CBD oil Solution of a solvent extract from Cannabis flowers and/or leaves dissolved in an edible oil; typically contains 1%–5% CBD
Hemp seed oil Edible, fatty oil produced from Cannabis seeds; contains no or only traces of cannabinoids
Dronabinol (trade names: Marinol and Syndros) Synthetic Δ 9 -THC
Nabilone (trade names: Cesamet and Canemes) Synthetic THC analog
Cannabidiol (trade name: Epidiolex) Highly purified (>98%), plant-derived CBD

The potential benefits of medicinal Cannabis for people living with cancer include the following:[2]

    effects. stimulation.
  • Pain relief.
  • Improved sleep.

Although few relevant surveys of practice patterns exist, it appears that physicians caring for cancer patients in the United States who recommend medicinal Cannabis do so predominantly for symptom management.[3] A growing number of pediatric patients are seeking symptom relief with Cannabis or cannabinoid treatment, although studies are limited.[4] The American Academy of Pediatrics has not endorsed Cannabis and cannabinoid use because of concerns about brain development.

This summary will review the role of Cannabis and the cannabinoids in the treatment of people with cancer and disease-related or treatment-related side effects. The National Cancer Institute (NCI) hosted a virtual meeting, the NCI Cannabis, Cannabinoids, and Cancer Research Symposium, on December 15–18, 2020. The seven sessions are summarized in the Journal of the National Cancer Institute Monographs and contain basic science and clinical information as well as a summary of the barriers to conducting Cannabis research.[5-11]

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Cannabis use for medicinal purposes dates back at least 3,000 years.[1-5] It was introduced into Western medicine in 1839 by W.B. O’Shaughnessy, a surgeon who learned of its medicinal properties while working in India for the British East India Company. Its use was promoted for reported analgesic, sedative, anti-inflammatory, antispasmodic, and anticonvulsant effects.

In 1937, the U.S. Treasury Department introduced the Marihuana Tax Act. This Act imposed a levy of $1 per ounce for medicinal use of Cannabis and $100 per ounce for nonmedical use. Physicians in the United States were the principal opponents of the Act. The American Medical Association (AMA) opposed the Act because physicians were required to pay a special tax for prescribing Cannabis, use special order forms to procure it, and keep special records concerning its professional use. In addition, the AMA believed that objective evidence that Cannabis was harmful was lacking and that passage of the Act would impede further research into its medicinal worth.[6] In 1942, Cannabis was removed from the U.S. Pharmacopoeia because of persistent concerns about its potential to cause harm.[2,3] Recently, there has been renewed interest in Cannabis by the U.S. Pharmacopeia.[7]

In 1951, Congress passed the Boggs Act, which for the first time included Cannabis with narcotic drugs. In 1970, with the passage of the Controlled Substances Act, marijuana was classified by Congress as a Schedule I drug. Drugs in Schedule I are distinguished as having no currently accepted medicinal use in the United States. Other Schedule I substances include heroin, LSD, mescaline, and methaqualone.

Despite its designation as having no medicinal use, Cannabis was distributed by the U.S. government to patients on a case-by-case basis under the Compassionate Use Investigational New Drug program established in 1978. Distribution of Cannabis through this program was closed to new patients in 1992.[1-4] Although federal law prohibits the use of Cannabis, Figure 1 below shows the states and territories that have legalized Cannabis use for medical purposes. Additional states have legalized only one ingredient in Cannabis, such as cannabidiol (CBD), and are not included in the map. Some medical marijuana laws are broader than others, and there is state-to-state variation in the types of medical conditions for which treatment is allowed.[8]

Enlarge Figure 1. A map showing the U.S. states and territories that have approved the medical use of Cannabis. Last updated: 10/14/2021

The main psychoactive constituent of Cannabis was identified as delta-9-tetrahydrocannabinol (THC). In 1986, an isomer of synthetic delta-9-THC in sesame oil was licensed and approved for the treatment of chemotherapy-associated nausea and vomiting under the generic name dronabinol. Clinical trials determined that dronabinol was as effective as or better than other antiemetic agents available at the time.[9] Dronabinol was also studied for its ability to stimulate weight gain in patients with AIDS in the late 1980s. Thus, the indications were expanded to include treatment of anorexia associated with human immunodeficiency virus infection in 1992. Clinical trial results showed no statistically significant weight gain, although patients reported an improvement in appetite.[10,11] Another important cannabinoid found in Cannabis is CBD.[12] This is a nonpsychoactive cannabinoid, which is an analog of THC.

In recent decades, the neurobiology of cannabinoids has been analyzed.[13-16] The first cannabinoid receptor, CB1, was identified in the brain in 1988. A second cannabinoid receptor, CB2, was identified in 1993. The highest expression of CB2 receptors is located on B lymphocytes and natural killer cells, suggesting a possible role in immunity. Endogenous cannabinoids (endocannabinoids) have been identified and appear to have a role in pain modulation, control of movement, feeding behavior, mood, bone growth, inflammation, neuroprotection, and memory.[17]

Nabiximols (Sativex), a Cannabis extract with a 1:1 ratio of THC:CBD, is approved in Canada (under the Notice of Compliance with Conditions) for symptomatic relief of pain in advanced cancer and multiple sclerosis.[18] Nabiximols is an herbal preparation containing a defined quantity of specific cannabinoids formulated for oromucosal spray administration with potential analgesic activity. Nabiximols contains extracts from two Cannabis plant varieties. The extracts mixture is standardized to the concentrations of the psychoactive delta-9-THC and the nonpsychoactive CBD. The preparation also contains other, more minor cannabinoids, flavonoids, and terpenoids.[19] Canada, New Zealand, and most countries in western Europe also approve nabiximols for spasticity of multiple sclerosis, a common symptom that may include muscle stiffness, reduced mobility, and pain, and for which existing therapy is unsatisfactory.

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Laboratory/Animal/Preclinical Studies

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis species (e.g., Cannabis sativa L.).[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biological activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic, anti-inflammatory, and anxiolytic activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo.[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] Two reviews summarize the molecular mechanisms of action of cannabinoids as antitumor agents.[13,14] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. For example, these compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats, while they protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[9]

See also  CBD Oil For Anxiety

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in HCC.[15] Both agents reduced the viability of HCC cells in vitro and demonstrated antitumor effects in HCC subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]

An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic mammary cells.[18] Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[19,20]

CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[21] In this experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In a subsequent study, the investigators found that the antiproliferative effect of CBD was counteracted by selective CB1 but not CB2 receptor antagonists, suggesting an involvement of CB1 receptors.[22]

Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression in tumor cells has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[23] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[24,25]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[26] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[27-30]

CBD may also enhance uptake of cytotoxic drugs into malignant cells. Activation of transient receptor potential vanilloid type 2 (TRPV2) has been shown to inhibit proliferation of human glioblastoma multiforme cells and overcome resistance to the chemotherapy agent carmustine. [31] One study showed that coadministration of THC and CBD over single-agent usage had greater antiproliferative activity in an in vitro study with multiple human glioblastoma multiforme cell lines.[32] In an in vitro model, CBD increased TRPV2 activation and increased uptake of cytotoxic drugs, leading to apoptosis of glioma cells without affecting normal human astrocytes. This suggests that coadministration of CBD with cytotoxic agents may increase drug uptake and potentiate cell death in human glioma cells. Also, CBD together with THC may enhance the antitumor activity of classic chemotherapeutic drugs such as temozolomide in some mouse models of cancer.[13,33] A meta-analysis of 34 in vitro and in vivo studies of cannabinoids in glioma reported that all but one study confirmed that cannabinoids selectively kill tumor cells.[34]

Antiemetic Effects

Preclinical research suggests that emetic circuitry is tonically controlled by endocannabinoids. The antiemetic action of cannabinoids is believed to be mediated via interaction with the 5-hydroxytryptamine 3 (5-HT3) receptor. CB1 receptors and 5-HT3 receptors are colocalized on gamma-aminobutyric acid (GABA)-ergic neurons, where they have opposite effects on GABA release.[35] There also may be direct inhibition of 5-HT3 gated ion currents through non–CB1 receptor pathways. CB1 receptor antagonists have been shown to elicit emesis in the least shrew that is reversed by cannabinoid agonists.[36] The involvement of CB1 receptor in emesis prevention has been shown by the ability of CB1 antagonists to reverse the effects of THC and other synthetic cannabinoid CB1 agonists in suppressing vomiting caused by cisplatin in the house musk shrew and lithium chloride in the least shrew. In the latter model, CBD was also shown to be efficacious.[37,38]

Appetite Stimulation

Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[39] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[40]


Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. Cannabinoids produce analgesia through supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways.[41] The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[42] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[43,44]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[45-47] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[48]

Cannabinoids have been shown to prevent chemotherapy-induced neuropathy in animal models exposed to paclitaxel, vincristine, or cisplatin.[49-51]

Anxiety and Sleep

The endocannabinoid system is believed to be centrally involved in the regulation of mood and the extinction of aversive memories. Animal studies have shown CBD to have anxiolytic properties. It was shown in rats that these anxiolytic properties are mediated through unknown mechanisms.[52] Anxiolytic effects of CBD have been shown in several animal models.[53,54]

The endocannabinoid system has also been shown to play a key role in the modulation of the sleep-waking cycle in rats.[55,56]

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  40. Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PUBMED Abstract]
  41. Baker D, Pryce G, Giovannoni G, et al.: The therapeutic potential of cannabis. Lancet Neurol 2 (5): 291-8, 2003. [PUBMED Abstract]
  42. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]
  43. Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PUBMED Abstract]
  44. Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PUBMED Abstract]
  45. Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PUBMED Abstract]
  46. Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PUBMED Abstract]
  47. Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PUBMED Abstract]
  48. Khasabova IA, Gielissen J, Chandiramani A, et al.: CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22 (5-6): 607-16, 2011. [PUBMED Abstract]
  49. Ward SJ, McAllister SD, Kawamura R, et al.: Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 171 (3): 636-45, 2014. [PUBMED Abstract]
  50. Rahn EJ, Makriyannis A, Hohmann AG: Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol 152 (5): 765-77, 2007. [PUBMED Abstract]
  51. Khasabova IA, Khasabov S, Paz J, et al.: Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. J Neurosci 32 (20): 7091-101, 2012. [PUBMED Abstract]
  52. Campos AC, Guimarães FS: Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199 (2): 223-30, 2008. [PUBMED Abstract]
  53. Crippa JA, Zuardi AW, Hallak JE: [Therapeutical use of the cannabinoids in psychiatry]. Rev Bras Psiquiatr 32 (Suppl 1): S56-66, 2010. [PUBMED Abstract]
  54. Guimarães FS, Chiaretti TM, Graeff FG, et al.: Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100 (4): 558-9, 1990. [PUBMED Abstract]
  55. Méndez-Díaz M, Caynas-Rojas S, Arteaga Santacruz V, et al.: Entopeduncular nucleus endocannabinoid system modulates sleep-waking cycle and mood in rats. Pharmacol Biochem Behav 107: 29-35, 2013. [PUBMED Abstract]
  56. Pava MJ, den Hartog CR, Blanco-Centurion C, et al.: Endocannabinoid modulation of cortical up-states and NREM sleep. PLoS One 9 (2): e88672, 2014. [PUBMED Abstract]

Human/Clinical Studies

Cannabis Pharmacology

When oral Cannabis is ingested, there is a low (6%–20%) and variable oral bioavailability.[1,2] Peak plasma concentrations of delta-9-tetrahydrocannabinol (THC) occur after 1 to 6 hours and remain elevated with a terminal half-life of 20 to 30 hours. Taken by mouth, delta-9-THC is initially metabolized in the liver to 11-OH-THC, a potent psychoactive metabolite. Inhaled cannabinoids are rapidly absorbed into the bloodstream with a peak concentration in 2 to 10 minutes, declining rapidly for a period of 30 minutes and with less generation of the psychoactive 11-OH metabolite.

Cannabinoids are known to interact with the hepatic cytochrome P450 enzyme system.[3,4] In one study, 24 cancer patients were treated with intravenous irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal Cannabis taken in the form of an herbal tea for 15 consecutive days, starting 12 days before the second treatment.[4] The administration of Cannabis did not significantly influence exposure to and clearance of irinotecan or docetaxel, although the herbal tea route of administration may not reproduce the effects of inhalation or oral ingestion of fat-soluble cannabinoids.

Highly concentrated THC or cannabidiol (CBD) oil extracts are being illegally promoted as potential cancer cures.[5] These oils have not been evaluated in any clinical trials for anticancer activity or safety. Because CBD is a potential inhibitor of certain cytochrome P450 enzymes, highly concentrated CBD oils used concurrently with conventional therapies that are metabolized by these enzymes could potentially increase toxicity or decrease the effectiveness of these therapies.[6,7]

Cancer Risk

A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with Cannabis smoking.

A pooled analysis of three case-cohort studies of men in northwestern Africa (430 cases and 778 controls) showed a significantly increased risk of lung cancer among tobacco smokers who also inhaled Cannabis.[8]

A large, retrospective cohort study of 64,855 men aged 15 to 49 years from the United States found that Cannabis use was not associated with tobacco-related cancers and a number of other common malignancies. However, the study did find that, among nonsmokers of tobacco, ever having used Cannabis was associated with an increased risk of prostate cancer.[9]

A population-based case-control study of 611 lung cancer patients revealed that chronic low Cannabis exposure was not associated with an increased risk of lung cancer or other upper aerodigestive tract cancers and found no positive associations with any cancer type (oral, pharyngeal, laryngeal, lung, or esophageal) when adjusting for several confounders, including cigarette smoking.[10]

A systematic review assessing 19 studies that evaluated premalignant or malignant lung lesions in persons 18 years or older who inhaled Cannabis concluded that observational studies failed to demonstrate statistically significant associations between Cannabis inhalation and lung cancer after adjusting for tobacco use.[11] In the review of the published meta-analyses, the National Academies of Sciences, Engineering, and Medicine (NASEM) report concluded that there was moderate evidence of no statistical association between Cannabis smoking and the incidence of lung cancer.[12]

Epidemiologic studies examining one association of Cannabis use with head and neck squamous cell carcinomas have also been inconsistent in their findings. A pooled analysis of nine case-control studies from the U.S./Latin American International Head and Neck Cancer Epidemiology (INHANCE) Consortium included information from 1,921 oropharyngeal cases, 356 tongue cases, and 7,639 controls. Compared with those who never smoked Cannabis, Cannabis smokers had an elevated risk of oropharyngeal cancers and a reduced risk of tongue cancer. These study results both reflect the inconsistent effects of cannabinoids on cancer incidence noted in previous studies and suggest that more work needs to be done to understand the potential role of human papillomavirus infection.[13] A systematic review and meta-analysis of nine case-control studies involving 13,931 participants also concluded that there was insufficient evidence to support or refute a positive or negative association between Cannabis smoking and the incidence of head and neck cancers.[14]

With a hypothesis that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems, the association between Cannabis use and incidence of testicular germ cell tumors (TGCTs) has been examined.[15-17] Three population-based case-control studies reported an association between Cannabis use and elevated risk of TGCTs, especially nonseminoma or mixed-histology tumors.[15-17] However, the sample sizes in these studies were inadequate to address Cannabis dose by addressing associations with respect to recency, frequency, and duration of use. In a study of 49,343 Swedish men aged 19 to 21 years enrolled in the military between 1969 and 1970, participants were asked once at the time of conscription about their use of Cannabis and were followed up for 42 years.[18] This study found no evidence of a significant relation between “ever” Cannabis use and the development of testicular cancer, but did find that “heavy” Cannabis use (more than 50 times in a lifetime) was associated with a 2.5-fold increased risk. Limitations of the study were that it relied on indirect assessment of Cannabis use; and no information was collected on Cannabis use after the conscription-assessment period or on whether the testicular cancers were seminoma or nonseminoma subtypes. These reports established the need for larger, well-powered, prospective studies, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCTs.

An analysis of 84,170 participants in the California Men’s Health Study was performed to investigate the association between Cannabis use and the incidence of bladder cancer. During 16 years of follow-up, 89 Cannabis users (0.3%) developed bladder cancer compared with 190 (0.4%) of the men who did not report Cannabis use (P < .001). After adjusting for age, race, ethnicity, and body mass index, Cannabis use was associated with a 45% reduction in bladder cancer incidence (hazard ratio, 0.55; 95% confidence interval (CI), 0.33–1.00).[19]

A comprehensive Health Canada monograph on marijuana concluded that while there are many cellular and molecular studies that provide strong evidence that inhaled marijuana is carcinogenic, the epidemiologic evidence of a link between marijuana use and cancer is still inconclusive.[20]

Patterns of Cannabis Use Among Cancer Patients

A cross-sectional survey of cancer patients seen at the Seattle Cancer Care Alliance was conducted over a 6-week period between 2015 and 2016.[21] In Washington State, Cannabis was legalized for medicinal use in 1998 and for recreational use in 2012. Of the 2,737 possible participants, 936 (34%) completed the anonymous questionnaire. Twenty-four percent of patients considered themselves active Cannabis users. Similar numbers of patients inhaled (70%) or used edibles (70%), with dual use (40%) being common. Non–mutually exclusive reasons for Cannabis use were physical symptoms (75%), neuropsychiatric symptoms (63%), recreational use/enjoyment (35%), and treatment of cancer (26%). The physical symptoms most commonly cited were pain, nausea, and loss of appetite. The majority of patients (74%) stated that they would prefer to obtain information about Cannabis from their cancer team, but less than 15% reported receiving information from their cancer physician or nurse.

Data from 2,970 Israeli cancer patients who used government-issued Cannabis were collected over a 6-month period to assess for improvement in baseline symptoms.[22] The most improved symptoms from baseline include the following:

  • Nausea and vomiting (91.0%). (87.5%).
  • Restlessness (87.5%). and depression (84.2%). (82.1%).
  • Headaches (81.4%).

Before treatment initiation, 52.9% of patients reported pain scores in the 8 to 10 range, while only 4.6% of patients reported this intensity at the 6-month assessment time point. It is difficult to assess from the observational data if the improvements were caused by the Cannabis or the cancer treatment.[22] Similarly, a study of a subset of cancer patients in the Minnesota medical Cannabis program explored changes in the severity of eight symptoms (i.e., anxiety, appetite loss, depression, disturbed sleep, fatigue, nausea, pain, and vomiting) experienced by these patients.[23]. Significant symptomatic improvements were noted (38.4%–56.2%) in patients with each symptom. Because of the observational and uncontrolled nature of this study, the findings are not generalizable, but as the authors suggested, may be useful in designing more rigorous research studies in the future.

Forty-two percent of women (257 of 612) with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea and vomiting (46%).[24] Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians.

A retrospective study from Israel of 50 pediatric oncology patients who were prescribed medicinal Cannabis over an 8-year period reported that the most common indications include the following:[25]

  • Nausea and vomiting.
  • Depressed mood.
  • Sleep disturbances.
  • Poor appetite and weight loss.
  • Pain.

Most of the patients (n = 30) received Cannabis in the form of oral oil drops, with some of the older children inhaling vaporized Cannabis or combining inhalation with oral oils. Structured interviews with the parents, and their child when appropriate, revealed that 40 participants (80%) reported a high level of general satisfaction with the use of Cannabis with infrequent short-term side effects.[25] Survey studies revealed that the majority of responding pediatricians in the United States and Canada supported the use of medical Cannabis for symptom management in patients with cancer.[26,27]

Cancer Treatment

No ongoing clinical trials of Cannabis as a treatment for cancer in humans were identified in a PubMed search. The first published trial of any cannabinoid in patients with cancer was a small pilot study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme, which demonstrated no significant clinical benefit.[28,29] A small double-blind exploratory phase IB study was conducted in the United Kingdom that used nabiximols, a 1:1 ratio of THC:CBD in a Cannabis-based medicinal extract oromucosal spray, in conjunction with dose-dense temozolomide in treating patients with recurrent glioblastoma multiforme.[30][Level of evidence: 1iA] Of the 27 patients enrolled, 6 were part of an open-label group and 21 were part of a randomized group (12 treated with nabiximols and 9 treated with placebo). Progression-free survival at 6 months was seen in 33% of patients in both arms of the study. However, 83.3% of the patients who received nabiximols were alive at 1 year compared with 44.4% of the patients who received placebo (P = .042). The investigators cautioned that this early-phase study was not powered for a survival endpoint. Overall survival rates at 2 years continued to favor the nabiximols arm (50%) compared with the placebo arm (22%) (these rates included results for the 6 patients in the open-label group who received nabiximols).[30]

In a 2016 consecutive case series study, nine patients with varying stages of brain tumors, including six with glioblastoma multiforme, received CBD 200 mg twice daily in addition to surgical excision and chemoradiation.[31][Level of evidence: 3iiiA] The authors reported that all but one of the cohort remained alive at the time of publication. However, the heterogeneity of the brain tumor patients probably contributed to the findings.

Another Israeli group postulated that the anti-inflammatory and immunosuppressive effects of CBD might make it a valuable adjunct in the treatment of acute graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation. The authors investigated CBD 300 mg/d in addition to standard GVHD prophylaxis in 48 adult patients who had undergone transplantation predominantly for acute leukemia or myelodysplastic syndrome (NCT01385124 and NCT01596075).[32] The combination of CBD with standard GVHD prophylaxis was found to be safe. Compared with 101 historical controls treated with standard prophylaxis, patients who received CBD appeared to have a lower incidence of grade II to grade IV GVHD, suggesting that a randomized controlled trial (RCT) is warranted.

Clinical data regarding Cannabis as an anticancer agent in pediatric use is limited to a few case reports.[33,34]

Antiemetic Effect


Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting (N/V) remain distressing side effects for cancer patients and their families. Dronabinol, a synthetically produced delta-9-THC, was approved in the United States in 1986 as an antiemetic to be used in cancer chemotherapy. Nabilone, a synthetic derivative of delta-9-THC, was first approved in Canada in 1982 and is now also available in the United States.[35] Both dronabinol and nabilone have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of N/V associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic therapy. Numerous clinical trials and meta-analyses have shown that dronabinol and nabilone are effective in the treatment of N/V induced by chemotherapy.[36-39] The National Comprehensive Cancer Network Guidelines recommend cannabinoids as breakthrough treatment for chemotherapy-related N/V.[40] The American Society for Clinical Oncology (ASCO) antiemetic guidelines updated in 2017 recommends that the FDA-approved cannabinoids, dronabinol or nabilone, be used to treat N/V that is resistant to standard antiemetic therapies.[41]

One systematic review studied 30 randomized comparisons of delta-9-THC preparations with placebo or other antiemetics from which data on efficacy and harm were available.[42] Oral nabilone, oral dronabinol, and intramuscular levonantradol (a synthetic analog of dronabinol) were tested. Inhaled Cannabis trials were not included. Among all 1,366 patients included in the review, cannabinoids were found to be more effective than the conventional antiemetics prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Cannabinoids, however, were not more effective for patients receiving very low or very high emetogenic chemotherapy. Side effects included a feeling of being high, euphoria, sedation or drowsiness, dizziness, dysphoria or depression, hallucinations, paranoia, and hypotension.[42]

Another analysis of 15 controlled studies compared nabilone with placebo or available antiemetic drugs.[43] Among 600 cancer patients, nabilone was found to be superior to prochlorperazine, domperidone, and alizapride, with nabilone favored for continuous use.

A Cochrane meta-analysis of 23 RCTs reviewed studies conducted between 1975 and 1991 that investigated dronabinol or nabilone, either as monotherapy or as an adjunct to the conventional dopamine antagonists that were the standard antiemetics at that time.[44] The chemotherapy regimens involved drugs with low, moderate, or high emetic potential. The meta-analysis graded the quality of evidence as low for most outcomes. The review concluded that individuals were more likely to report complete absence of N/V when they received cannabinoids compared with placebo, although they were more likely to withdraw from the study because of an adverse event. Individuals reported a higher preference for cannabinoids than placebo or prochlorperazine. There was no difference in the antiemetic effect of cannabinoids when compared with prochlorperazine. The authors concluded that Cannabis-based medications may be useful for treating refractory chemotherapy-induced N/V; however, they cautioned that their assessment may change with the availability of newer antiemetic regimens.

At least 50% of patients who receive moderately emetogenic chemotherapy may experience delayed chemotherapy-induced N/V. Although selective neurokinin 1 antagonists that inhibit substance P have been approved for delayed N/V, a study was conducted before their availability to assess dronabinol, ondansetron, or their combination in preventing delayed-onset chemotherapy-induced N/V.[45] Ondansetron, a serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, is one of the mainstay agents in the current antiemetic armamentarium. In this trial, the primary objective was to assess the response 2 to 5 days after moderately to severely emetogenic chemotherapy. Sixty-one patients were analyzed for efficacy. The total response—a composite endpoint—including nausea intensity, vomiting/retching, and use of rescue medications, was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) when compared with placebo (20%). Nausea absence was greater in the active treatment groups (dronabinol 71%, ondansetron 64%, combination therapy 53%) when compared with placebo (15%; P < .05 vs. placebo for all). Occurrence rates for nausea intensity and vomiting/retching episodes were the lowest in patients treated with dronabinol, suggesting that dronabinol compares favorably with ondansetron in this situation where a substance P inhibitor would currently be the drug of choice.

For more information, see the Cannabis section in Nausea and Vomiting Related to Cancer Treatment.


Three trials have evaluated the efficacy of inhaled Cannabis in chemotherapy-induced N/V.[46-49] In two of the studies, inhaled Cannabis was made available only after dronabinol failure. In the first trial, no antiemetic effect was achieved with marijuana in patients receiving cyclophosphamide or doxorubicin,[46] but in the second trial, a statistically significant superior antiemetic effect of inhaled Cannabis versus placebo was found among patients receiving high-dose methotrexate.[47] The third trial was a randomized, double-blind, placebo-controlled, crossover trial involving 20 adults in which both inhaled marijuana and oral THC were evaluated. One-quarter of the patients reported a favorable antiemetic response to the cannabinoid therapies. This latter study was reported in abstract form in 1984. A full report, detailing the methods and outcomes apparently has not been published, which limits a thorough interpretation of the significance of these findings.[48]

Newer antiemetics (e.g., 5-HT3 receptor antagonists) have not been directly compared with Cannabis or cannabinoids in cancer patients. However, the Cannabis-extract oromucosal spray, nabiximols, formulated with 1:1 THC:CBD was shown in a small pilot randomized, placebo-controlled, double-blinded clinical trial in Spain to treat chemotherapy-related N/V.[50][Level of evidence: 1iC]

ASCO antiemetic guidelines updated in 2017 state that evidence remains insufficient to recommend medical marijuana for either the prevention or treatment of N/V in patients with cancer who receive chemotherapy or radiation therapy.[41]

Appetite Stimulation

Anorexia, early satiety, weight loss, and cachexia are problems experienced by cancer patients. Such patients are faced not only with the disfigurement associated with wasting but also with an inability to engage in the social interaction of meals.


Four controlled trials have assessed the effect of oral THC on measures of appetite, food appreciation, calorie intake, and weight loss in patients with advanced malignancies. Three relatively small, placebo-controlled trials (N = 52; N = 46; N = 65) each found that oral THC produced improvements in one or more of these outcomes.[51-53] The one study that used an active control evaluated the efficacy of dronabinol alone or with megestrol acetate compared with that of megestrol acetate alone for managing cancer-associated anorexia.[54] In this randomized, double-blind study of 469 adults with advanced cancer and weight loss, patients received 2.5 mg of oral THC twice daily, 800 mg of oral megestrol daily, or both. Appetite increased by 75% in the megestrol group and weight increased by 11%, compared with a 49% increase in appetite and a 3% increase in weight in the oral THC group after 8 to 11 weeks of treatment. The between-group differences were statistically significant in favor of megestrol acetate. Furthermore, the combined therapy did not offer additional benefits beyond those provided by megestrol acetate alone. The authors concluded that dronabinol did little to promote appetite or weight gain in advanced cancer patients compared with megestrol acetate.


In trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase in caloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods.[55,56]

Despite patients’ great interest in oral preparations of Cannabis to improve appetite, there is only one trial of Cannabis extract used for appetite stimulation. In an RCT, researchers compared the safety and effectiveness of orally administered Cannabis extract (2.5 mg THC and 1 mg CBD), THC (2.5 mg), or placebo for the treatment of cancer-related anorexia-cachexia in 243 patients with advanced cancer who received treatment twice daily for 6 weeks. Results demonstrated that although these agents were well tolerated by these patients, no differences were observed in patient appetite or quality of life among the three groups at this dose level and duration of intervention.[57]

No published studies have explored the effect of inhaled Cannabis on appetite in cancer patients.



Pain management improves a patient’s quality of life throughout all stages of cancer. Through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists, the mechanisms of cannabinoid-induced analgesia have been analyzed.[58][Level of evidence:1iC] The CB1 receptor is found in the central nervous system (CNS) and in peripheral nerve terminals.[59] CB2 receptors are located mainly in peripheral tissue and are expressed in only low amounts in the CNS. Whereas only CB1 agonists exert analgesic activity in the CNS, both CB1 and CB2 agonists have analgesic activity in peripheral tissue.[60,61]

Cancer pain results from inflammation, invasion of bone or other pain-sensitive structures, or nerve injury. When cancer pain is severe and persistent, it is often resistant to treatment with opioids.

Two studies examined the effects of oral delta-9-THC on cancer pain. The first, a double-blind, placebo-controlled study involving ten patients, measured both pain intensity and pain relief.[62] It was reported that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with substantial analgesic effects, with antiemetic effects and appetite stimulation.

In a follow-up, single-dose study involving 36 patients, it was reported that 10 mg doses of delta-9-THC produced analgesic effects during a 7-hour observation period that were comparable to 60 mg doses of codeine, and 20 mg doses of delta-9-THC induced effects equivalent to 120 mg doses of codeine.[63] Higher doses of THC were found to be more sedating than codeine.

Another study examined the effects of a plant extract with controlled cannabinoid content in an oromucosal spray. In a multicenter, double-blind, placebo-controlled study, the THC:CBD nabiximols extract and THC extract alone were compared in the analgesic management of patients with advanced cancer and with moderate-to-severe cancer-related pain. Patients were assigned to one of three treatment groups: THC:CBD extract, THC extract, or placebo. The researchers concluded that the THC:CBD extract was efficacious for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids.[64] In a randomized, placebo-controlled, graded-dose trial, opioid-treated cancer patients with poorly controlled chronic pain demonstrated significantly better control of pain and sleep disruption with THC:CBD oromucosal spray at lower doses (1–4 and 6–10 sprays/d), compared with placebo. Adverse events were dose related, with only the high-dose group (11–16 sprays/d) comparing unfavorably with the placebo arm. These studies provide promising evidence of an adjuvant analgesic effect of THC:CBD in this opioid-refractory patient population and may provide an opportunity to address this significant clinical challenge.[65] An open-label extension study of 43 patients who had participated in the randomized trial found that some patients continued to obtain relief of their cancer-related pain with long-term use of the THC:CBD oromucosal spray without increasing their dose of the spray or the dose of their other analgesics.[66]

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An observational study assessed the effectiveness of nabilone in advanced cancer patients who were experiencing pain and other symptoms (anorexia, depression, and anxiety). The researchers reported that patients who used nabilone experienced improved management of pain, nausea, anxiety, and distress when compared with untreated patients. Nabilone was also associated with a decreased use of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, gabapentin, dexamethasone, metoclopramide, and ondansetron.[67]


Animal studies have suggested a synergistic analgesic effect when cannabinoids are combined with opioids. The results from one pharmacokinetic interaction study have been reported. In this study, 21 patients with chronic pain were administered vaporized Cannabis along with sustained-release morphine or oxycodone for 5 days.[68] The patients who received vaporized Cannabis and sustained-release morphine had a statistically significant decrease in their mean pain score over the 5-day period; those who received vaporized Cannabis and oxycodone did not. These findings should be verified by further studies before recommendations favoring such an approach are warranted in general clinical practice.

Neuropathic pain is a symptom cancer patients may experience, especially if treated with platinum-based chemotherapy or taxanes. Two RCTs of inhaled Cannabis in patients with peripheral neuropathy or neuropathic pain of various etiologies found that pain was reduced in patients who received inhaled Cannabis, compared with those who received placebo.[69,70] A retrospective analysis examined the effect of Cannabis on chemotherapy-induced peripheral neuropathy (CIPN) in Israeli cancer patients who received oxaliplatin-based regimens for gastrointestinal malignancies.[71][Level of evidence: 2Diii] Patients were divided into three groups on the basis of their exposure to Cannabis: Cannabis-first group (received Cannabis before starting oxaliplatin), oxaliplatin-first group (received oxaliplatin before starting Cannabis), and controls (no Cannabis use). A significant difference in grade 2 to 3 CIPN was seen between the Cannabis-exposed patients (15.3%) and controls (27.9%) (P < .001). The neuropathy-sparing effect was more pronounced among those treated with Cannabis first (75%) compared with those who received oxaliplatin first (46.2%) (P < .001). Some limitations of this study were its retrospective design and documentation of Cannabis use as qualitative, not quantitative.

A randomized, placebo-controlled, crossover, pilot study of nabiximols in 16 patients with chemotherapy-induced neuropathic pain showed no significant difference between the treatment and placebo groups. A responder analysis, however, demonstrated that five patients reported a reduction in their pain of at least 2 points on an 11-point scale, suggesting that a larger follow-up study may be warranted.[72]

One real-world randomized controlled trial explored Cannabis use in patients with advanced cancer who received care in a community oncology practice setting (148 screened; 30 randomized; 18 analyzed).[73] Once certified by their oncologists, participants were randomized to receive early Cannabis (EC) or delayed start of medical Cannabis (DC) for 3 months as part of a state-sponsored Cannabis program. The EC group had stable opioid usage compared with the DC group who had an increase in opioid usage during the 3-month study period. Overall, there were no significant changes in quality of life or symptom scores between the groups, with no overall Cannabis-related adverse events. Limitations included a variety of cancer types and no consistent use of Cannabis products (108 different Cannabis products were dispensed during the study period).

Anxiety and Sleep


In a small pilot study of analgesia involving ten patients with cancer pain, secondary measures showed that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with anxiolytic effects.[62][Level of evidence: 1iC]

A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[52][Level of evidence: 1iC]


Patients often experience mood elevation after exposure to Cannabis, depending on their previous experience. In a five-patient case series of inhaled Cannabis that examined analgesic effects in chronic pain, it was reported that patients who self-administered Cannabis had improved mood, improved sense of well-being, and less anxiety.[74]

Another common effect of Cannabis is sleepiness. A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[52]

Seventy-four patients with newly diagnosed head and neck cancer self-described as current Cannabis users were matched to 74 nonusers in a Canadian study investigating quality of life using the EuroQol-5D and Edmonton Symptom Assessment System instruments.[75] Cannabis users had significantly lower scores in the anxiety/depression (difference, 0.74; 95% CI, 0.557–0.930) and pain/discomfort (difference, 0.29; 95% CI, 0.037–1.541) domains. Cannabis users were also less tired, had more appetite, and better general well-being.

A single center, phase II, double-blind study of two ratios (1:1 [THC:CBD] and 4:1 [THC:CBD]) of an oral medical Cannabis oil enrolled patients with recurrent or inoperable high-grade glioma. Investigators assessed the side effects and Functional Assessment of Cancer Therapy-Brain (FACT-Br) at baseline and 12 weeks as a primary outcome.[76] There was no difference in the primary endpoint; however, some significant differences were noted in the subscores of the FACT-Br (i.e., physical, functional, and sleep favored the 1:1 ratio) and these endpoints would be appropriate for future research.

Clinical Studies of Cannabis and Cannabinoids

Table 2. Clinical Studies of Cannabis a

Reference Trial Design Condition or Cancer Type Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) b Results c Concurrent Therapy Used d Level of Evidence Score e
5-HT3 = 5-hydroxytryptamine 3; CINV = chemotherapy-induced nausea and vomiting; N/V = nausea and vomiting; RCT = randomized controlled trial.
a For additional information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
b Number of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.
c Strongest evidence reported that the treatment under study has activity or otherwise improves the well-being of cancer patients.
d Concurrent therapy for symptoms treated (not cancer).
e For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[76] RCT High-grade gliomas 88; 45 (1:1), 43 (4:1); None No difference in the primary endpoint Dexamethasone, temozolomide, bevacizumab, lomustine 1iC
[46] RCT CINV 8; 8; None No antiemetic effect reported No 1iC
[47] RCT CINV 15; 15; None Decreased N/V No 1iiC
[50] Pilot RCT CINV 16; 7; 9 Decreased delayed N/V 5-HT3 receptor antagonists 1iC
[68] Nonrandomized trial Chronic pain 21;10 (morphine), 11 (oxycodone); None Decreased pain Yes, morphine, oxycodone 2C
[75] Prospective cohort study Anxiety, pain, depression, loss of appetite 148; 74; 74 Decreased pain, anxiety, depression, increased appetite Unknown 2C
Table 3. Clinical Studies of Cannabinoids a

Reference Trial Design Condition or Cancer Type Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control) b Results c Concurrent Therapy Used d Level of Evidence Score e
CBD = cannabidiol; No. = number; NSAIDs = nonsteroidal anti-inflammatory drugs; QoL = quality of life; RCT = randomized controlled trial; THC = delta-9-tetrahydrocannabinol.
a For additional information and definition of terms, see text and the NCI Dictionary of Cancer Terms.
b Number of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.
c Strongest evidence reported that the treatment under study has activity or otherwise improves the well-being of cancer patients.
d Concurrent therapy for symptoms treated (not cancer).
e For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
[54] RCT Cancer-associated anorexia 469; dronabinol 152, megestrol acetate 159, or both 158; None Megestrol acetate provided increased appetite and weight gain, among advanced cancer patients compared with dronabinol alone No 1iC
[52] Pilot RCT Appetite 21; 11; 10 THC, compared with placebo, improved and enhanced taste and smell No 1iC
[57] RCT Cancer-related anorexia-cachexia syndrome 243; Cannabis extract 95, THC 100; 48 No differences in patients’ appetite or QoL were found No 1iC
[77] RCT Appetite 139; 72; 67 Increase in appetite No 1iC
[53] RCT Anorexia 47; 22; 25 Increased calorie intake No 1iC
[62] RCT Pain 10; 10; None Pain relief No 1iC
[64] RCT Pain 177; 60 (THC:CBD), 58 (THC); 59 THC:CBD extract group had reduced pain Yes, opioids 1iC
[65] RCT Pain 360; 269; 91 Decreased pain in low-dose group Yes, opioids 1iC
[66] Open-label extension Pain 43; 39 (THC:CBD), 4 (THC), None Decreased pain Yes, opioids 2C
[67] Observational study Pain 112; 47; 65 Decreased pain Yes, opioids, NSAIDs, gabapentin 2C

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  44. Smith LA, Azariah F, Lavender VT, et al.: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev (11): CD009464, 2015. [PUBMED Abstract]
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  56. Foltin RW, Fischman MW, Byrne MF: Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11 (1): 1-14, 1988. [PUBMED Abstract]
  57. Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 24 (21): 3394-400, 2006. [PUBMED Abstract]
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  64. 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 39 (2): 167-79, 2010. [PUBMED Abstract]
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  67. Maida V, Ennis M, Irani S, et al.: Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol 6 (3): 119-24, 2008. [PUBMED Abstract]
  68. Abrams DI, Couey P, Shade SB, et al.: Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90 (6): 844-51, 2011. [PUBMED Abstract]
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Adverse Effects

Cannabis and Cannabinoids

Because cannabinoid receptors, unlike opioid receptors, are not located in the brainstem areas controlling respiration, lethal overdoses from Cannabis and cannabinoids do not occur.[1-4] However, cannabinoid receptors are present in other tissues throughout the body, not just in the central nervous system, and adverse effects include the following:

  • Tachycardia. . injection.
  • Bronchodilation.
  • Muscle relaxation.
  • Decreased gastrointestinal motility.

Although cannabinoids are considered by some to be addictive drugs, their addictive potential is considerably lower than that of other prescribed agents or substances of abuse.[2,4] The brain develops a tolerance to cannabinoids.

Withdrawal symptoms such as irritability, insomnia with sleep electroencephalogram disturbance, restlessness, hot flashes, and, rarely, nausea and cramping have been observed. However, these symptoms appear to be mild compared with withdrawal symptoms associated with opiates or benzodiazepines, and the symptoms usually dissipate after a few days.

Unlike other commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate (half-life 1–3 days), so even abrupt cessation of cannabinoid intake is not associated with rapid declines in plasma concentrations that would precipitate severe or abrupt withdrawal symptoms or drug cravings.

Cannabidiol (CBD) is an inhibitor of cytochrome P450 isoforms in vitro. Because many anticancer therapies are metabolized by these enzymes, highly concentrated CBD oils used concurrently could potentially increase the toxicity or decrease the effectiveness of these therapies.[5,6]

Since Cannabis smoke contains many of the same components as tobacco smoke, there are valid concerns about the adverse pulmonary effects of inhaled Cannabis. A longitudinal study in a noncancer population evaluated repeated measurements of pulmonary function over 20 years in 5,115 men and women whose smoking histories were known.[7] While tobacco exposure was associated with decreased pulmonary function, the investigators concluded that occasional and low-cumulative Cannabis use was not associated with adverse effects on pulmonary function (forced expiratory volume in the first second of expiration [FEV1] and forced vital capacity [FVC]).

Interactions With Conventional Cancer Therapies

The potential for cytochrome P450 interactions with highly concentrated oil preparations of delta-9-tetrahydrocannabinol and/or cannabidiol is a concern.[8] Few pharmacokinetic interaction studies have been conducted with Cannabis or cannabinoids and conventional cancer therapies. A small study investigated the effect of Cannabis tea in 24 patients who received irinotecan or docetaxel.[9] Administration of the Cannabis tea did not significantly influence exposure to and clearance of either intravenous agent.

An Israeli retrospective observational study assessed the impact of Cannabis use during nivolumab immunotherapy.[10] One hundred forty patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma received the checkpoint inhibitor nivolumab (89 patients received nivolumab alone and 51 patients received nivolumab plus Cannabis). In a multivariate model, Cannabis was the only significant factor that reduced the response rate to immunotherapy (37.5% in patients who received nivolumab alone compared with 15.9% in patients who received nivolumab plus Cannabis [odds ratio, 3.13; 95% confidence interval, 1.24–8.1; P = .016]). There was no difference in progression-free survival or overall survival. A subsequent prospective observational study from the same investigators followed 102 patients with metastatic cancers initiating immunotherapy.[11][Level of evidence: 2Dii] Sixty-eight patients received immunotherapy alone while 34 patients used Cannabis during immunotherapy. Over half of the patients in each group had stage IV non-small cell lung cancer. Cannabis users were less likely to receive immunotherapy as a first-line intervention (24%) compared with nonusers (46%) (P = .03). Cannabis users showed a significantly lower percentage of clinical benefit (39% of Cannabis users with complete or partial responses or stable disease compared with 59% of nonusers [P = .035]). In this analysis, the median time to tumor progression was 3.4 months in Cannabis users compared with 13.1 months in nonusers and the overall survival was 6.4 months in Cannabis users compared with 28.5 months in nonusers. The investigators also noted that Cannabis users reported a lower rate of overall treatment-related adverse experiences compared with nonusers, with fewer immune-related adverse events (P = .057). The investigators postulated that this finding may be related to the possible immunosuppressive effects of Cannabis and concluded that Cannabis consumption should be carefully considered in patients with advanced malignancies who are treated with immunotherapy. Limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants.

  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. The Haworth Press, 2002.
  3. Sutton IR, Daeninck P: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec. [PUBMED Abstract]
  4. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PUBMED Abstract]
  5. Yamaori S, Okamoto Y, Yamamoto I, et al.: Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39 (11): 2049-56, 2011. [PUBMED Abstract]
  6. Jiang R, Yamaori S, Okamoto Y, et al.: Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28 (4): 332-8, 2013. [PUBMED Abstract]
  7. Pletcher MJ, Vittinghoff E, Kalhan R, et al.: Association between marijuana exposure and pulmonary function over 20 years. JAMA 307 (2): 173-81, 2012. [PUBMED Abstract]
  8. Kocis PT, Vrana KE: Delta-9-tetrahydrocannabinol and cannabidiol drug-drug interactions. Med Cannabis Cannabinoids 3 (1): 61-73, 2020.
  9. Engels FK, de Jong FA, Sparreboom A, et al.: Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12 (3): 291-300, 2007. [PUBMED Abstract]
  10. Taha T, Meiri D, Talhamy S, et al.: Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies. Oncologist 24 (4): 549-554, 2019. [PUBMED Abstract]
  11. Bar-Sela G, Cohen I, Campisi-Pinto S, et al.: Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers (Basel) 12 (9): , 2020. [PUBMED Abstract]

Summary of the Evidence for Cannabis and Cannabinoids

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for people with cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

  • Be published in a peer-reviewed scientific journal.
  • Report on therapeuticoutcome or outcomes, such as tumorresponse, improvement in survival, or measured improvement in quality of life.
  • Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of possible scores and additional information about levels of evidence analysis of Complementary and Alternative Medicine (CAM) treatments for people with cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

  • Several controlled clinical trials have been performed, and meta-analyses of these support a beneficial effect of cannabinoids (dronabinol and nabilone) on chemotherapy-induced nausea and vomiting (N/V) compared with placebo. Both dronabinol and nabilone are approved by the U.S. Food and Drug Administration for the prevention or treatment of chemotherapy-induced N/V in cancer patients but not for other symptom management.
  • There have been ten clinical trials on the use of inhaledCannabis in cancer patients that can be divided into two groups. In one group, four small studies assessed antiemetic activity, but each explored a different patient population and chemotherapy regimen. One study demonstrated no effect, the second study showed a positive effect versus placebo, and the report of the third study did not provide enough information to characterize the overall outcome as positive or neutral. Consequently, there are insufficient data to provide an overall level of evidence assessment for the use of Cannabis for chemotherapy-induced N/V. Apparently, there are no published controlled clinical trials on the use of inhaled Cannabis for other cancer-related or cancer treatment–related symptoms.
  • An increasing number of trials are evaluating the oromucosal administration of Cannabis plant extract with fixed concentrations of cannabinoid components, with national drug regulatory agencies in Canada and in some European countries that issue approval for cancer pain.
  • At present, there is insufficient evidence to recommend inhaling Cannabis as a treatment for cancer-related symptoms or cancer treatment–related symptoms or cancer treatment-related side effects; however, additional research is needed.

Changes to This Summary (06/07/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added text to state that the National Cancer Institute (NCI) hosted a virtual meeting, the NCI Cannabis, Cannabinoids, and Cancer Research Symposium, on December 15–18, 2020. The seven sessions are summarized in the Journal of the National Cancer Institute Monographs and contain basic science and clinical information as well as a summary of the barriers to conducting Cannabis research (cited Ellison et al, Sexton et al., Cooper et al., Braun et al., Ward et al., McAllister et al., and Abrams et al., as references 5, 6, 7, 8, 9, 10, and 11, respectively).

Added text to state that 42% of women with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain, insomnia, anxiety, stress, and nausea and vomiting (cited Weiss et al. as reference 24). Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians.

Added text to state that survey studies revealed that the majority of responding pediatricians in the United States and Canada supported the use of medical Cannabis for symptom management in patients with cancer (cited Oberoi et al. and Ananth et al. as references 26 and 27, respectively).

Added text to state that limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Cannabis and cannabinoids in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cannabis and Cannabinoids. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq. Accessed . [PMID: 26389198]

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