Use of cannabinoid receptor agonists in cancer
therapy as palliative and curative agents
Simona Pisanti, PhD, Doctora, Anna Maria Malfitano, PhD, Doctora,
Claudia Grimaldi, PhD, Doctora, Antonietta Santoro, PhD, Doctora,
Patrizia Gazzerro, PhD, Doctora, Chiara Laezza, PhD, Doctorb,
Maurizio Bifulco, MD, Professora,*
aDepartment of Pharmaceutical Sciences, University of Salerno, Italy
bIstituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy
Cannabinoids (the active components of Cannabis sativa) and their
derivatives have received renewed interest in recent years due to
their diverse pharmacological activities. In particular, cannabinoids
offer potential applications as anti-tumour drugs, based on the
ability of some members of this class of compounds to limit cell
proliferation and to induce tumour-selective cell death. Although
synthetic cannabinoids may have pro-tumour effects in vivo due to
their immunosuppressive properties, predominantly inhibitory
effects on tumour growth and migration, angiogenesis, metastasis,
and also inflammation have been described. Emerging evidence
suggests that agonists of cannabinoid receptors expressed by
tumour cells may offer a novel strategy to treat cancer. In this
chapter we review the more recent results generating interest in
the field of cannabinoids and cancer, and provide novel sugges-
tions for the development, exploration and use of cannabinoid
agonists for cancer therapy, not only as palliative but also as
? 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ39 089 969742; Fax: þ39 089 969602.
E-mail address: firstname.lastname@example.org (M. Bifulco).
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/beem
1521-690X/$ – see front matter ? 2009 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131
An overview of the endocannabinoid system
The therapeutic and psychotropic actions of the plant Cannabis sativa were first described about
4000 years ago in India, a long time before the discovery of the endocannabinoid system.1By the 19th
century cannabis extracts had gained widespread use for medicinal purposes until 1937, when
concerns about the dangers of abuse led to the banning of marijuana for further medicinal use in the
United States. However, over the last 40 years the isolation and characterization of the psychoactive
component of C. sativa, D9-tetrahydrocannabinol (D9-THC) represented a challenging research task,
awakening renewed interest in its use for pharmacotherapy.2To date, about 60 different plant terpeno-
phenols more or less structurally related to THC have been isolated and defined as cannabinoids. They
include cannabidiol (CBD), cannabinol, cannabigerol, and cannabichromene. The majority of these lack
psychoactivity. The chemical and biological characterization of these principles encouraged the
synthesis of novel analogous compounds, similar to phytocannabinoids or with different chemical
structures, such as classic and non-classic cannabinoids and aminoalkylindoles.3Finally, studies on
cannabinoids have led to the discovery of the endogenous arachidonic acid derivatives now known as
Endocannabinoids are lipid molecules, ubiquitously expressed, containing long-chain poly-
unsaturated fatty acids, amides, esters and ethers; the first-characterized compounds were ananda-
mide (AEA) and 2-arachidonoylglycerol (2-AG). More recently, several other bioactive lipid mediators
have been described: 2-arachidonoyl-glyceryl-ether (noladin ether), o-arachidonoyl-ethanolamine
(virodhamine), N-arachidonoyl-dopamine, oleamide, and the ‘endocannabinoid-like’ N-palmitoyle-
thanolamine (PEA), N-oleoylethanolamine (OEA) and N-stearoylethanolamine (SEA).4,5
Physiological or pathological stimuli induce the synthesis and immediate release of endocannabi-
noids which can subsequently activate cannabinoid receptors, either after previous release into the
extracellular space or directly moving within the cell membrane. It seems clear that the regulation of
endocannabinoid signalling is tightly controlled by their synthesis, release, uptake and degradation,
and all the enzymes involved in these pathways are potential targets for pharmacological intervention
in a wide range of diseases where a lack of balance in the endocannabinoid system has been reported.
Mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease,
neuropathic pain, multiple sclerosis and spinal cord injury, cancer, atherosclerosis, myocardial
infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome and osteoporosis are just
some of the diseases in which an altered endocannabinoid system plays an interesting role for phar-
Endocannabinoids, as well as phytocannabinoids and their synthetic analogues, show different
selectivities for the two-cannabinoid receptor types (CB1 and CB2) that have so far been cloned from
mammalian tissues. Both the CB1 and CB2 genes encode a seven-transmembrane-domain protein
belonging to the Gi/oprotein-coupled receptor family.7The receptors display different patterns of
expression; CB1 receptor is preferentially expressed in the central nervous system and in several
peripheral organs, whereas CB2 receptor is the predominant form expressed in immune cells and is
unrelated to cannabinoid psychoactive effects. Different structural classes of cannabinoid receptor
agonists have the unique ability to activate different signalling cascades which, in turn, influence
agonist efficacy. Among these pathways, inhibition of adenylate cyclase8stimulation of mitogen-
activated protein kinase (MAPK)9and phosphatidylinositol-3-kinase pathway10and, in the case of CB1,
modulation of ion channels have been reported.11
Current thoughts about the endocannabinoid system in cancer
Modulating the activity of proteins and nuclear factors involved in cell proliferation, differentiation
and apoptosis, the endocannabinoid signalling system controls, among the other effects, cell survival,
death and neoplastic transformation.12,13Recent studies have therefore proposed that the endo-
cannabinoid system could be an attractive anticancer target, and the cannabinoid agonists might
directly inhibit tumour growth in vitro and in vivo. Several cannabinoids – including D9-THC and
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131 118
cannabidiol, synthetic cannabinoid agonists (HU210, JWH133, WIN-55,212-2), endocannabinoids
(anandamide, its congeners and 2-AG), and endocannabinoid transport or degradation inhibitors
(VDM-11 and AA-5-HT) – have been shown to inhibit tumour growth and progression of several types
of cancers, including glioma, glioblastoma multiforme, breast, prostate and thyroid cancer, colon
carcinoma, leukaemia and lymphoid tumours (see Table 1).13The proposed mechanisms are complex
and different, depending on the tumour type, and may involve induction of apoptosis in tumour cells,
anti-proliferative action through the suppression of mitogenic signals, and anti-metastatic effect
through inhibition of neo-angiogenesis and tumour cell migration.13,14Moreover, the effects,
depending on the specific type of agonist and target tissue, have been reported to be CB1, CB2 or TRPV1
receptor-dependent or receptor-independent (e.g. cyclooxygenase, lipid rafts), all leading to activate
different downstream signalling pathways.
Anti-proliferative effects occur possibly through inhibition of proliferative pathways such as
adenylyl cyclase and cAMP/protein kinase A pathway16, cell cycle blockade with induction of the
cyclin-dependent kinase inhibitor p27kip134, decrease in epidermal growth factor receptor (EGF-R)
expression and/or attenuation of EGF-R tyrosine kinase activity41,24, decrease in the activity and/or
expression of nerve growth factor, prolactin or vascular endothelial growth factor tyrosine kinase
receptors.15,17,34The pro-apoptotic effect of cannabinoids in tumour cells is complex and may involve
increased synthesis of the pro-apoptotic sphingolipid ceramide28, ceramide-dependent up-regulation
of the stress protein p8 and several downstream stress-related genes expressed in the endoplasmic
reticulum (ATF-4, CHOP, and TRB3)48, prolonged activation of the Raf-1/extracellular signal-regulated
kinase cascade28, and inhibition of Akt28,30, c-Jun NH2-terminal kinase and p38 mitogen-activated
protein kinase.28,32More importantly, systemic or local treatment with cannabinoids inhibited the
growth of various types of tumours or tumour cell xenografts in vivo, including lung carcinoma46,
glioma28,29, thyroid epithelioma33, lymphoma37, and skin carcinoma45in mice. Inhibition of the
formation of colon polyps in the genetic model of Apcþ/?mice and further of precancerous aberrant
crypt foci induced by the potent carcinogen azoxymethane in mice have also been reported
recently.43,44Based on the in vivo efficacy, it has been suggested that anti-tumour efficacy of canna-
binoid-related drugs could be partially ascribed to the inhibition of tumour metastatic spreading and
neo-angiogenesis in several models.34,41,49Cannabinoid agonists also directly inhibited angiogenesis
induced by basic fibroblast growth factor (bFGF) in vitro and in vivo in a CB1-dependent manner50, and
reduced the invasiveness of different cancer cell lines through the increased expression of tissue
inhibitor of metalloproteinases TIMP-1.51In addition to cannabinoid agonists, inhibitors of endo-
cannabinoid transport or degradation (VDM-11 and AA-5-HT) have been shown to inhibit tumour
growth and progression in numerous types of cancer, enhancing the levels of endocannabinoids in the
Cannabinoids, immune suppression, and potential increased cancer risk
In the light of the available literature, potential tumour-promoting effects of cannabinoid agonists
have been taken into account and analysed. Hart et al47reported pro-proliferative effects of
cannabinoids in different cancer cell lines at submicromolar doses, very low if compared to both the
anti-proliferative and pro-apoptotic doses widely reported (in the micromolar range) and to the
concentration achieved in vivo for most anticancer drugs during a chemotherapy protocol.47However,
the same study documented that at micromolar concentrations cannabinoids induced cancer-cell
apoptosis, in agreement with previous reports. These results highlight a likely bimodal action of
cannabinoid agonists on cancer cell growth, with low concentrations being pro-proliferative and high
concentrations having anti-proliferative effects. More appropriate is the concern about the immuno-
suppressive properties of cannabinoids in vivo through CB2 receptor stimulation in immune cells and
the risk of the anti-tumour immune response inhibition. Indeed cannabinoids have been shown to
modulate a variety of immune-cell functions in humans and animals, and more recently have been
shown to modulate T-helper-cell development, chemotaxis, and tumour development.52Many of these
effects occur through cannabinoid receptor CB2 signalling mechanisms and the modulation of
cytokines and other gene products. THC has been reported to exert immunosuppressive effects in vitro
and in vivo on macrophages, NK cells and T lymphocytes. Endocannabinoid synthetic analogues
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131119
Effect of cannabinoid agonists in cancer treatment.
(cell type/animal model)
(concentration or dose)
Mechanism of actionReference
Human breast cancer cell lines
(MCF-7; EFM-19; T47D)
AEA (2–10 mM)
2-AG (2–10 mM)
HU210 (?4 mM)
AEA (?2 mM)
2-AG, HU210 (?1 mM)
Inhibition of the mitogen-induced stimulation
of the G0/G1–S phase
Inhibition of NGF-induced proliferation
Inhibition adenylyl cyclase; down-regulation
S phase arrest; induction Chk1 intra-S phase
Inhibition of adhesion and migration
Human breast cancer cell line
Human breast cancer cell line
Mouse breast cancer cell line
Human breast cancer cell lines
Mouse mammary carcinoma
Human breast cancer cell lines
(MCF-7; T47D; MDA-MB-
Human breast cancer cell lines
Human breast cancer cell lines
AEA (10 mM)
AEA (10 mM and
In vivo, reduction of number and dimension of
Increased tumour growth and metastasis
THC (?5 mM)
In vivo, decreased anti-tumour immune
G2/M phase transition blockade through Cdc2
and apoptosis induction
THC (?12 mM)
Rimonabant (0.1 mM
and 0.7 mg/kg/dose)
Inhibition of proliferation; apoptosis induction
Inhibition of proliferation; G1 arrest
In vivo, growth inhibition of breast xenografts
prostate cancer cells
cancer cells (LNCaP)
cancer cells (LNCaP)
cancer cells (LNCaP)
AEA, R-(þ)-MET (?2 mM) Inhibition of mitogen-induced proliferation,
Inhibition of mitogen-induced proliferation,
Dose- and time-dependent induction of
apoptosis; decreased expression of AR and PSA
Increased proliferation and AR expression
THC (1 mM)
AEA, R-(þ)-MET (?2 mM)
WIN-55,212-2 (?2.5 mM)
Glioma and brain cancers:
Rat glioma cell line (C6) THC (1 mM) Apoptosis via ceramide de-novo synthesis
In vivo, regression of C6-derived glioma
Apoptosis via ceramide de-novo synthesis
WIN-55,212-2 (15 mM)
JWH-133 (50 mg/d)
Apoptosis via activation of caspase cascade
In vivo, inhibited growth of tumours induced in
Decreased proliferation and increased cell death
Human astrocytoma (grade IV)
multiforme cell line (GBM)
Human neuroglioma cells
THC (1 mM)
R-(þ)-MET (1–10 mM)
thyroid cells (KiMol)
Thyroid tumour xenografts
In vivo, inhibited growth of tumours induced in
In vivo, inhibited growth of thyroid tumour
xenografts induced in athymic mice
In vivo, inhibited development of lung
In vivo, inhibited growth of thyroid tumour
xenografts induced in athymic mice
Experimental lung metastases
Thyroid tumour xenograftsMet-F-AEA (0.5 mg/kg/d);
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131120
suppress T-cell proliferation, inhibit interferong (IFN-g) production, and shift the balance of T-helper-1
(Th1)/T-helper-2 (Th2) cytokines.53
Although most of the studies propose an anti-tumour efficacy of cannabinoid agonists, a few
studies suggest a potential increased cancer risk following cannabinoid exposure due to a biasing
toward Th2 immunity. The immune response to tumours is primarily mediated by Th1 response.
Skewing of the immune response from the cell-mediated Th1 response to the humoral-mediated Th2
response may lead to a positive environment for tumour growth. Increased levels of these cytokines
and a shift toward the Th2 immune response have been associated with breast and lung cancers,
directly correlated with suppression of the immune response.54T cells secreting type-2 cytokines,
including IL-10, inhibit cell-mediated immunity and anti-tumour responses. In contrast, T cells
producing type-1 cytokines, including IL-2 and IFN-g, are potent activators of cell-mediated immunity.
Regulation of cytokine production profiles allows a controlled balance between stimulation and
suppression of cell-mediated responses. THC and other cannabinoid agonists may exert their immu-
nosuppressive effects through disruption of these homeostatic mechanisms by inhibiting the
production of type-1 cytokines and promoting type-2 cytokine production by lymphocytes.55Host
immunity plays an important role in limiting tumour growth.56In murine lung cancer models, biasing
toward Th2 immunity was reported57, showing that THC promotes tumourigenicity and limits
immunogenicity in vivo by up-regulating the immune inhibitory cytokines interleukin 10 (IL-10) and
Table 1 (continued)
(cell type/animal model)
(concentration or dose)
Mechanism of actionReference
Lymphoma U937 cells
Lymphoma cell lines
AEA (10 mM)
THC (10 mM), HU210
THC (1–5 mM);
THC (14–25 mM); CBD
Apoptosis induction via TRPV1
Apoptosis induction via CB2
Mantle-cell lymphoma cell
Growth inhibition; apoptosis induction
Human leukaemia cellsApoptosis via CB2
C6 glioma cells
Growth inhibition; apoptosis induction
Colorectal carcinoma cells
AEA (2.5 mM), 2AG (1 mM),
HU210 (0.1 mM), VDM-11,
AA-5-HT (10 mM)
AEA (25 mM)
Inhibition of proliferation
Colorectal carcinoma cells
aberrant crypt foci (ACF) in
the mouse colon
Cell death via COX-2
AA-5-HT (5 mg/kg),
HU210 (0.1 mg/kg)
Inhibition of ACF formation; caspase-3
(10 mg/kg), AM251
Inhibition of colon polyps
Stimulation of colon polyps
Mouse skin carcinoma cells
Lung cancer cells (NCI-H292)
Glioblastoma cell line
Pancreatic tumour cells (Panc1;
THC 100 mg/kg
THC (0.1–0.3 mM)
In vivo, inhibited growth of tumours induced in
THC (2 mM and
Apoptosis induction through ceramide
In vivo, inhibited growth of xenografts and
AEA, anandamide; NGF, nerve growth factor; PRLr, prolactin receptor; THC, tetrahydrocannabinol; MET, methanandamide;
AR, androgen receptor; PSA, prostate-specific antigen; TRPV1, transient receptor potential vanilloid type 1; CBD, cannabidiol;
COX-2, cyclooxygenase 2.
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131 121
tumour growth factor b (TGF-b). Furthermore, lymphocytes from THC-treated mice transferred the
effect to normal mice, resulting in accelerated tumour growth similar to that observed in the 7THC-
treated mice. These effects were CB2-receptor-dependent. A similar CB2-dependent shift to Th2
cytokines was demonstrated in response to THC in activated peripheral-blood T-cell cultures.58A
possible key could be the relative levels of CB receptors expressed by tumour cells. When these levels
are high, both tumour and immune cells are targeted by cannabinoid agonists, and the consequent
effect is the inhibition of tumour growth. In contrast, tumour cells expressing low or undetectable
levels of CB receptors are resistant to the anti-proliferative effects and immunosuppression through
CB2 prevails. A study demonstrated that exposure to THC led to increased tumour growth and
metastasis of the mouse mammary carcinoma 4T1, which expresses low to undetectable levels of
cannabinoid receptors CB1 and CB2; these effects were due to inhibition of the specific anti-tumour
immune response in vivo. Furthermore, exposure toTHC led to increased production of Th2-associated
cytokines, IL-4 and IL-10. Such findings suggest that cannabinoid agonists used either recreationally or
medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other
cancers that do not express cannabinoid receptors and are resistant to THC-induced apoptosis.37
Relevance of cannabinoid receptor levels in cancer
Cannabinoid receptor levels seem to be a fundamental element for the growth-inhibitory effects of
cannabinoid agonists. It has been reported that the expression of CB1 receptor was regulated in
opposite ways in normal and malignant cells. This pattern of expression seems to be a common
mechanism for the general protection of normal cells from the pro-apoptotic and anti-proliferative
effects of cannabinoid agonists.13THC-induced apoptosis in several human cancer cell lines, but
showed less efficacy in non-transformed cell counterparts that might be protected from cell
death.25,28,31,45Therefore, a relevant issue seems to be the evaluation of cannabinoid receptor
expression in tumour versus normal tissues in order to achieve a significant anti-tumour effect with
cannabinoid agonists without immunosuppression, and also for the prognostic value that CB receptor
levels could have alone or in association with other recognized prognostic markers.
To date there have been few studies in this field. Analyses of astrocytomas demonstrated that 70% of
the tumours express CB1 and/or CB2, and the extent of CB2 expression was directly related to tumour
malignancy.29In hepatocellular carcinoma, over-expression of CB1 and CB2 receptors correlated with
CB2 inbreastcancer,whereacorrelation amongCB2 expression,histological grade of tumourand other
markers of prognostic and predictive value – such as oestrogen receptor, progesterone receptor, and
ERBB2/HER-2 oncogene – has been observed.21In gliomas a higher expression of CB2 compared to CB1
was reported and was related to tumour grade.61Interestingly, it has recently been reported that CB1
expression was silenced in human colorectal cancer due to promoter methylation.44Regulation of CB
receptors by factors naturally expressed in the tumour microenvironment is intriguing, and must be
progression. Studies at the promoter level of CB receptor genes could therefore be very informative.
Moreover, the trafficking and recycling of CB receptors and their sublocalization and compartmentali-
zation (e.g. lipid rafts/caveolae, organuli) in tumour cells compared with normal cells could be useful.
Anti-inflammatory activity of cannabinoid agonists and cancer prevention
The link between inflammation and cancer was noticed 150 years ago by Virchow, who indicated
that cancers frequently occur at sites of chronic inflammation.62Recently it has turned out that acute
inflammation contributes to the regression of cancer.63However, accumulated epidemiological studies
support the idea that chronic inflammatory diseases are frequentlyassociated with an increased risk of
cancer.62–64It has been realized that the development of cancer from inflammation might be a process
driven by inflammatory cells as well as a variety of mediators, including cytokines, chemokines, and
enzymes, which altogether establish an inflammatory microenvironment.64As discussed above,
although this host response may suppress tumours, it may also facilitate cancer development via
multiple signalling pathways.65
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131 122
Studies examining the effect of cannabinoid-based drugs on immunity have shown that many
cellular and cytokine mechanisms are suppressed by these agents, leading to the hypothesis that these
drugs may be of value in the management of chronic inflammatory diseases. Evidence of the role of
cannabimimetic compounds – such as anandamide (AEA), 2-arachidonoylglycerol (2-AG) and palmi-
toyethanolamide (PEA) – in the control of inflammation and proliferation of tumour cells has been
described. AEA was found to enhance the release of the anti-inflammatory cytokine IL-6 from astro-
cytes infected with Theiler’s murine encephalomyelitis virus.66The anti-inflammatory effects of PEA
have been also described.67In particular, reduction of substance-P-induced mast-cell degranulation
and extravasation, passive cutaneous anaphylaxis-induced extravasation, formalin and dextran-
induced oedema, and carrageenan-induced oedema thermal hyperalgesia were found, and the last
effect being described also for AEA.68A synthetic agonist at CB1 and CB2, HU-210, exerts an anti-
inflammatory effect. It was shown that this compound abolished abdominal pain associated with
pancreatitis and also reduced inflammation and decreased tissue pathology in mice without producing
central, adverse effects.69
Furthermore, treatment with HU-210 or genetic ablation of the
endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) resulted in protection against
2,4-dinitrobenzene sulphonic-acid-induced colitis, thus suggesting that the endocannabinoid system
could be a promising therapeutic target for the treatment of intestinal disease characterized by
excessive inflammatory responses.70
Along with anti-inflammatory effects, anti-tumour properties of endocannabinoids have been
reported; in particular, an inhibitory effect of AEA on migration of both colon carcinoma cells and T
lymphocytes has been described, thus suggesting relevance as a tool to prevent metastasis formation
without depreciatory effects on the immune system of cancer patients.71An exception is UVB-induced
inflammation. Very recent work showed that the CB1/2 receptors are required in the induction of the
proinflammatory-cascade-dependent skin tumour development in response to UVB. It was shown that
the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflam-
mation and a marked decrease in UVB-induced skin carcinogenesis.72
Although the use of cannabinoids-related drugs for medicinal purposes could be limited by
concerns about their psychotropic effects, they have shown a fair safety profile, especially with respect
to current chemotherapeutics which all display toxic adverse effects.
Despite the overall collected evidence on the therapeutic potential of cannabinoids and related
drugs in several types of cancer, only a single pilot clinical study has been performed so far, and the
results have been published recently.73This phase-I/II clinical trial was approved by the Spanish
Ministry of Health in 2002 and was aimed at evaluating the safety profile of THC administration and its
anti-tumour activity in a cohort of nine terminally ill patients affected by recurrent glioblastoma
multiforme, an aggressive primary brain tumour with poor prognosis (6–12 months survival) and no
efficacious treatment. The first goalof thestudy was to confirm the safetyof intracranial administration
of THC and the absence of significant psychotropiceffects at the used regimen.Moreover, the study was
reassuring about the possibility that cannabinoids could have tumour-promoting effects, since THC
administration did not induce tumour growth or decrease patient survival. THC decreased tumour-cell
proliferation, and also induced apoptosis; however, it had only a slight impact on the overall median
survival of the cohort (24 weeks). This pioneer study suffers some limitations due to its design. The
results are somewhat encouraging, and open the way to new studies with different characteristics. It
will be interesting in the future to perform other clinical trials aimed at evaluating the efficacy of
cannabinoid agonists (not limited to THC) in cancer treatment in different types of tumours. To opti-
mize the results, the protocols should involve large cohorts of patients, and combinatorial studies with
commonly used chemotherapeutic drugs could be interesting.
CB1 antagonism by rimonabant: unexpected anti-tumour efficacy
The role of the CB1–endocannabinoid axis in physiopathology is reflected in the ongoing develop-
ment of high-affinity CB1 antagonists and inverse agonists, in addition to cannabinoid agonists, as
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131 123
therapeutic drugs. The first highly selective CB1 receptor antagonist was discovered by Sanofi-aventis
and was the diarylpyrazole [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-
1H-pyrazole-3-carboxamide hydrochloride], so-called rimonabant (SR141716, Acomplia?), which
showed a number of beneficial pharmacological effects in several pathological situations: e.g. obesity,
metabolic syndrome, diabetes, nicotine dependence, and a plethora of unexpected biological effects in
vitro and in vivo.74It is noteworthy that most of the CB1 receptor antagonists developed to date,
of the tonic action of the endocannabinoids.75In some experiments, rimonabant has been found to
produce effects that are opposite in direction from those produced by cannabinoid receptor agonists.
syndrome management has raised the alarming question of the potential tumour-promoting effect of
cannabinoid antagonism. Rimonabant counteracts the anti-tumour effects of anandamide-related
compounds and other cannabinoid agonists in thyroid, breast and prostate cancers.19,26,34Unexpect-
edly, rimonabant per se showed a potential anti-tumour action in thyroid, mantle-cell lymphoma and
breast tumours both in vitro and in vivo.23,33,38Furthermore, rimonabant displayed anti-proliferative
properties in preadipocyte and hepatic myofibroblasts in vitro and in vivo.76,77At least in breast cancer
cells, the ability of rimonabant to early compartmentalize CB1 receptors in lipid rafts and segregate
represent a possible explanation for its anti-proliferative activity. It appears clear that either cannabi-
noid agonists or the antagonist/inverse agonist rimonabant targeting CB1 signalling display a compa-
rable inhibitoryefficacyoncancer growth,eventhoughthroughadifferentmechanism of action.Thisis
unsurprising, since there are multiple oncogenic cascades and potential tumour-suppressing targets.
Further studies will be necessary to ensure the efficacy of rimonabant and other CB1 receptor antag-
onists/inverse agonists as anticancer drugs. Positive results in this field could start the development of
selective antagonists unable to pass the blood–brain barrier in order to avoid the psychiatric effects,
above all major depression, which represent the major side-effects of rimonabant.
Cannabinoids in cancer therapy as palliative agents
The potential application of cannabinoid agonists as anticancer agents is still at the preclinical level.
Meanwhile the cannabinoids are emerging as valuable adjunctive agents for optimizing the
management of multiple symptoms of cancer and the treatment of therapy-related side-effects.
Indeed, while much about the pathophysiological mechanisms of the endocannabinoid system
remains unknown, available data support a broad spectrum of palliative properties, including appetite
stimulation, inhibition of nausea and emesis associated with chemotherapyor radiotherapy, pain relief,
mood amelioration, and relief from insomnia.78The commercially available cannabinoids target
ubiquitous cannabinoid receptors in the central (CB1) and peripheral (CB1 and CB2) nervous system.79
In the United States, two FDA-approved medicinal cannabis products are available: Marinol,
a synthetic form of THC (the most active ingredient in cannabis) and Cesamet, a synthetic THC
analogue. Both are currently approved for chemotherapy-induced nausea and vomiting in patient who
have failed to respond adequately to conventional anti-emetic compounds. Dronabinol is also
approved for the treatment of anorexia associated with AIDS. A third medicinal cannabis product,
Sativex (a combination of THC and CBD) is already approved and marketed in Canada as adjunctive
treatment for the symptomatic relief of neuropathic pain in multiple sclerosis.79Health Canada has
approved Sativex under its Notice of Compliance with conditions (NOC/c) policy. It is also available on
a named-patient basis in the United Kingdom and the Catalunya Autonomous Region of Spain. In the
USA, the lead indication for Sativex is cancer pain inpatients who have not been adequately relieved by
opioid medications, and in 2007 the first USAphase-III cancer pain trial with this drug started (Table 2).
Inhibition of chemotherapy-induced nausea and emesis
Two of the most prevalent side-effects of cancer and its treatment are chemotherapy-induced
nausea and vomiting (CINV); approximately one half of cancer patients will experience nausea or
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131124
vomiting during the disease. Control of CINV is mediated by multiple neurotransmitters, including
serotonin, dopamine, histamine, endorphins, acetylcholine, g-aminobutyric acid and cannabinoids.80
Cannabinoids are used for patients who have nausea and vomiting that are not responsive to standard
anti-emetic therapy. Cannabinoids not only interact with CB receptors but also with the dopaminergic,
serotonin, monoaminergic, noradrenergic and opioid system, important pathways involved in
emesis.81There is evidence that cannabinoids act on CB1 receptors in the dorsal–vagal complex of the
brainstem region controlling the vomiting reflex, and that endocannabinoids and their inactivating
enzymes are present in the gastrointestinal tract and might have a physiological role in the control of
emesis.82Clinical studies and case reports (the main ones listed inTable 3) have confirmed that natural
and synthetic THC are more effective than placebo. Cannabinoids are unlikely to be used as first-line
treatment for nausea and vomiting, but they may be use as adjuvant treatment to enhance the effects
of existing anti-emetic medications.
Pain has a negative impact on the life quality in cancer patients. Almost half of all patients with
cancer experience moderate to severe pain, and this increases in patients with metastatic or advanced
stages of cancer. This burden negatively impacts on their life quality, functional status and life
expectancy. Cancer pain is often treated with opioid drugs (e.g. codeine, morphine, and/or their
synthetic analogues); however, these drugs have dose-limiting side-effects.93The use of cannabinoids
to treat cancer pain may provide a novel therapeutic approach. Several studies have shown that
systemic administration of cannabinoids produces anti-nociception and attenuates hyperalgesia and
allodynia in animal models of acute and chronic pain.94Potenzieri et al demonstrated that tumour-
evoked hyperalgesia was dose-dependently attenuated by local administration of non-selective
cannabinoid receptor agonist WIN-55,212-2 into the tumour-bearing hind paw in a model of rodent
cancer pain.95Cannabinoids produce anti-nociception by activating CB1 receptors in the brain, the
spinal cord and nerve terminals. Endocannabinoids naturally function to suppress pain by inhibiting
nociceptive neurotransmission.96Clinical trials on cannabinoid analgesia are very heterogeneous;
nonetheless there are some human data to support the effectiveness of cannabinoids in alleviating pain
associated with cancer (Table 3). In particular, findings from propensity-score analysis of data obtained
from advanced cancer patients suggest that nabilone offers benefits beyond its original indication to
treat chemotherapy-induced nausea and vomiting. Nabilone administration improved management of
Available cannabinoid-containing drugs.
CannabinoidSource Registered name
and official status
IndicationsRoute of administration
Onset and duration
Nausea and vomiting
with sesame oil
30–60 min, 4–6 h
Nausea and vomiting
60–90 min, 8–12 h
THC & CBDIsolated from
conditions in Canada
in Spain and UK
of neuropathic pain
15–40 min, 2–4 h
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131125
pain and was associated with a lower overall use of drugs such as opioids and non-steroidal anti-
Health Canada approved Sativex in 2007, with conditions, as adjunctive analgesic treatment in
adult patients with advanced cancer who experience moderate to severe pain during the highest
tolerated dose of strong opioid therapy for persistent background pain. This authorization reflects the
promising nature of the clinical evidence which will be confirmed with further clinical trials on
Clinical studies and case reports of palliative properties of cannabinoids in cancer patients.
A prospective observational
study assessed the
effectiveness of adjuvant
nabilone therapy in
managing pain and
symptoms experienced by
advanced cancer patients
Phase-III clinical trials will test
thedrug’s ability totreatpain
in advanced cancer patients
who have not found relief
through conventional opioid
medications (e.g. codeine,
morphine, and/or their
NabilonePatients receiving nabilone experienced
reduced pain, nausea, and anxiety and
relief of overall distress. Beneficial but
non-significative effect on appetite
Sativex In progress
Dronabinol Dronabinol alone improved appetite in
almost 50% of patients
Dronabinol was as effective as ondansetron
in reducing nausea and vomiting; combination
of therapy was not more effective
Nabilone treatment improved pain, nausea,
appetite and several other symptoms
A significant increase in appetite and
decrease in nausea in most patients
No difference between cannabis, THC
5-day double-bind, placebo-
Appetite loss, weight loss
Appetite loss, weight loss
Appetite loss, weight loss in
patient with CACS
Nabilone Significant improvement in one case of intractable
neuropathic pain and on case of refractory CINV
Megestrol acetate was superior to dronabinol
Appetite loss/weight loss in
cancer patients with CACS
CINV eight children, aged 3–13
years with various
treated with different anti-
neoplastic drugs for up to 8
A phase-II study of D9-
appetite stimulation in
tested alone and in
a randomized, double-blind,
D8-THC Vomiting was completely prevented. The side-effects
observed were negligible
D9-THC THC is an effective appetite stimulant in patients
with advanced cancer. It is well tolerated at low doses
Dronabinol The combination was significantly more effective
than was either agent alone in controlling
chemotherapy-induced nausea and vomiting
CINV, chemotherapy-induced nausea and vomiting; CACS, cancer anorexia–cachexia syndrome; THC, tetrahydrocannabinol.
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131126
cannabinoids in the treatment of cancer pain – including terminal care – which are now in progress.
Indeed, the US FDA accepted GW’s Investigational New Drug (IND) Application for Sativex, allowing
GW to launch phase-III clinical trials in the United States. These trials will test the drug’s ability to
treat pain in advanced cancer patients who have not found relief through conventional opioid
Appetite stimulation (orexigenic effects)
Cancer-related anorexia and associated cachexia are prevalent manifestations of disease in
people with malignancies, and the cancer anorexia–cachexia syndrome (CACS) is an important
risk factor for morbidity and mortality in people with cancer. Many studies have reported that
THC and other cannabinoids have a stimulatory effect on appetite and increase food intake in
animals.97This circuit is well known, and the orexigenic effect occurs through the inhibition of
leptin at hypothalamic level.98Anecdotal information from cannabis smokers and numerous
clinical trials support the appetite-stimulating properties of THC. In fact, the synthetic cannabi-
noid dronabinol is approved by the FDA for the treatment of anorexia associated with weight loss
in AIDS patients.
Clinical evidence for the use of cannabinoids in patients with CACS is limited (Table 3). A
phase-II study of THC for appetite stimulation in cancer-associated anorexia showed that THC
is an effective stimulant in patient with advanced cancer.91In contrast, Jatoi et al demon-
strated that megestrol acetate (an orexigenic agent) provided palliation of anorexia in
advanced cancer patients superior to that of dronabinol alone, and that the combination
therapy did not confer additional benefit.89Moreover, it was showed that dronabinol produced
a small, although not significant, increase in body weight in residents of geriatric facilities.99
Finally, the first phase III in patients with CACS comparing the effects of cannabinoids with
placebo and standardized cannabis extract showed no differences between the three groups
for stimulation of appetite, quality of life, or secondary endpoint such as mood or nausea.87
Further research should elucidate the clinical relevance and the real benefit of cannabinoids
for cancer anorexia.
The discovery of the endocannabinoid system and the recognition of its potential impact in
a plethora of pathological conditions led to the development of therapeutic agents related to either
agonism or antagonism of CB1 and CB2 receptors, the majority of which are in preclinical studies. A
few medications that belong to the endocannabinoid system have been subjected to clinical studies
and are now available and useful as palliative drugs in disease states associated with cancer, such as
chemotherapy-induced nausea and vomiting, pain relief, and anorexia/weight loss. Cannabinoid
agonists show interesting potential as anticancer drugs, and the preclinical studies carried out so far
have yielded encouraging results in different in vitro and in vivo models of cancers. The use of
cannabinoid agonists as palliative drugs, and results obtained in the unique clinical trial in glioma
patients, has demonstrated that cannabinoid agonists show a good-safety profile. Although their use
in medicine could be limited by their known psychotropic effects, this could be bypassed by the
development of selective agonists devoid of psychotropic effects (such as cannabidiol) or unable to
pass the blood–brain barrier. It is noteworthy that THC delivery in glioma patients was safe and
achieved without psychoactive effects. Moreover, the potential adverse effects of cannabinoid
agonists are within the range believed acceptable for other drugs, especially anticancer drugs. It is
well known that the therapeutic activity of most anticancer drugs in clinical use is limited by their
general toxicity to proliferating cells, including normal cells. Novel cytotoxic agents with known
mechanisms of action have been developed, but they still lack tumour selectivity and have not been
therapeutically useful. Cannabinoid agonists do seem to selectively target tumour cells, while normal
cells are less sensitive or even protected. Further clinical studies will clarify their efficacy in treating
cancer in humans, not only as palliative drugs but also as therapeutic agents which could be used
alone or in combination with other chemotherapeutic drugs in order to avoid resistance and exert
S. Pisanti et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 117–131127
a more potent clinical impact. As our knowledge of the endocannabinoid system becomes more
defined, it can be expected that more drugs acting directly on this system will be available for
This study was supported by Associazione Educazione e Ricerca Medica Salernitana (ERMES).
Simona Pisanti was supported by a fellowship from FIRC (Italian Foundation for Cancer Research).
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