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of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations

Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors

two major cannabinoid-specific receptors—cb1 and cb2

transient receptor potential cation channel subfamily V, member 1

orphan G protein–coupled receptor 55

Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation

the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins

cardiovascular tone, energy metabolism, immunity, and reproduction

cannabinoids are well known to exert palliative effects in cancer patients

best-established use is the inhibition of chemotherapy-induced nausea and vomiting

thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer

cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue

cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer

pharmacologic activation of cannabinoid receptors decreases tumour growth

endocannabinoid signalling can also have a tumour-suppressive role

pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids

most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation

impair tumour angiogenesis and block invasion and metastasis

thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation

Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death

autophagy is important for cannabinoid antineoplastic activity

autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death

the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors

glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy

other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions

thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations

cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors

In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi

In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis

cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture

the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2

cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis

cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts

ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer

recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth

combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells

Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively

Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity

Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth

Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models

pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids

antitumoral agents

Aside from THC, C. sativa produces approximately 70 other cannabinoids, although, unlike THC, many of them exhibit little affinity for CB receptors (10, 20). Of interest, at least one of these components, namely, cannabinol (CBD; Supplementary Fig. 1), has been shown to reduce the growth of different types of tumor xenografts including gliomas

the combined administration of THC and CBD is being therapeutically explored (10, 20, 26), although its effects on the proliferation and survival of cancer cells have only been analyzed in vitro