326
Views
2
CrossRef citations to date
0
Altmetric
Review Articles

Cannabis as a potential compound against various malignancies, legal aspects, advancement by exploiting nanotechnology and clinical trials

, , , , , , ORCID Icon & show all
Pages 709-725 | Received 15 Jan 2022, Accepted 15 Mar 2022, Published online: 28 Mar 2022

References

  • Single convention on narcotic drugs; n.d.
  • Fanovich MA, Churio MS, Ramirez CL. Chapter 2 – Medicinal cannabis: Pharmaceutical forms and recent analytical methodologies. In: Comprehensive Analytical Chemistry [Internet]. 2020 Jan 1 [cited 2022 Mar 23]; vol. 90; pp. 31–63. Available from: https://app.dimensions.ai/details/publication/pub.1127593784
  • McPartland JM, Guy GW, Marzo VD. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014;9(3):e89566.
  • Bonini SA, Premoli M, Tambaro S, et al. Cannabis sativa: a comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol. 2018;227:300–315.
  • Szutorisz H, Hurd YL. Epigenetic effects of cannabis exposure. Biol Psychiatry. 2016;79(7):586–594.
  • Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–564.
  • Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65.
  • Jiang S, Fu Y, Williams J, et al. Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells. PLoS One. 2007;2(7):e641.
  • Deng L, Guindon J, Cornett BL, et al. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015;77(5):475–487.
  • Howlett AC, Barth F, Bonner TI, et al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202.
  • Glass M, Northup JK. Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol Pharmacol. 1999;56(6):1362–1369.
  • Galve-Roperh I, Sánchez C, Cortés ML, et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med. 2000;6(3):313–319.
  • Velasco G, Galve-Roperh I, Sánchez C, et al. Cannabinoids and ceramide: two lipids acting hand-by-hand. Life Sci. 2005;77(14):1723–1731.
  • Demuth DG, Molleman A. Cannabinoid signalling. Life Sci. 2006;78(6):549–563.
  • Qamri Z, Preet A, Nasser MW, et al. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther. 2009;8(11):3117–3129.
  • Ryberg E, Larsson N, Sjögren S, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092–1101.
  • O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 2007;152:576–582.
  • Haustrate A, Prevarskaya N, Lehen’kyi V. Role of the TRPV channels in the endoplasmic reticulum calcium homeostasis. Cells. 2020;9(2):317.
  • Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84(11):2477–2482.
  • Navarro G, Varani K, Reyes-Resina I, et al. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1-CB2 heteroreceptor complexes. Front Pharmacol. 2018;9:632.
  • Navarro G, Varani K, Lillo A, et al. Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors. Pharmacol Res. 2020;159:104940.
  • Izzo AA, Borrelli F, Capasso R, et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515–527.
  • DeLong GT, Wolf CE, Poklis A, et al. Pharmacological evaluation of the natural constituent of cannabis sativa, cannabichromene and its modulation by Δ(9)-tetrahydrocannabinol. Drug Alcohol Depend. 2010;112(1–2):126–133.
  • Turner CE, Elsohly MA. Biological activity of cannabichromene, its homologs and isomers. J Clin Pharmacol. 1981;21:283S–291S.
  • Pertwee RG, Howlett AC, Abood ME, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62(4):588–631.
  • Afrin F, Chi M, Eamens AL, et al. Cancers can hemp help? Low-THC cannabis and non-THC cannabinoids for the treatment of cancer. Cancers. 2020;12(4):1033.
  • Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci. 2016;7:19.
  • Thomas A, Baillie GL, Phillips AM, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–623.
  • Khan MI, Soboci|Ska AA, Czarnecka AM, et al. The therapeutic aspects of the endocannabinoid system (ECS) for cancer and their development: from nature to laboratory. Curr Pharm Des. 2016;22(12):1756–1766.
  • Maurya N, Velmurugan BK. Therapeutic applications of cannabinoids. Chem Biol Interact. 2018;293:77–88.
  • De Jong FA, Engels FK, Mathijssen RHJ, et al. Medicinal cannabis in oncology practice: still a bridge too far? J Clin Oncol. 2005;23(13):2886–2891.
  • Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers. 2007;4(8):1729–1743.
  • Hazekamp A, Ware MA, Muller-Vahl KR, et al. The medicinal use of cannabis and cannabinoids-an international cross-sectional survey on administration forms the Sativa-Indica dilemma view project SILCAAT and ESPRIT view project arno hazekamp hazekamp herbal consulting. J Psychoactive Drugs. 2013;45(3):199–210.
  • Tomko A, O'Leary L, Trask H, et al. Antitumor activity of abnormal cannabidiol and its analog O-1602 in taxol-resistant preclinical models of breast cancer. Front Pharmacol. 2019;10:1124.
  • Dumitru CA, Sandalcioglu IE, Karsak M. Cannabinoids in glioblastoma therapy: new applications for old drugs. Front Mol Neurosci. 2018;11:159.
  • Agarwal E, Chaudhuri A, Leiphrakpam PD, et al. Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and ezrin in colorectal cancer. BMC Cancer. 2014;14(1):145.
  • Cannabis also has beneficial effects on brain function. Google Scholar; n.d.
  • Malfitano AM, Ciaglia E, Gangemi G, et al. Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets. 2011;15(3):297–308.
  • Benz AH, Renné C, Maronde E, et al. Expression and functional relevance of cannabinoid receptor 1 in Hodgkin lymphoma. PLOS One. 2013;8(12):e81675.
  • Tomko AM, Whynot EG, Ellis LD, et al. Anti-cancer potential of cannabinoids, terpenes, and flavonoids present in cannabis. Cancers. 2020;12(7):1985–1981.
  • Ngwa W, Kumar R, Moreau M, et al. Nanoparticle drones to target lung cancer with radiosensitizers and cannabinoids. Front Oncol. 2017;7:208.
  • Singh D, Dilnawaz F, Sahoo SK. Challenges of moving theranostic nanomedicine into the clinic. Nanomedicine. 2020;15(2):111–114.
  • Mulvihill JJ, Cunnane EM, Ross AM, et al. Drug delivery across the blood-brain barrier: recent advances in the use of nanocarriers. Nanomedicine. 2020;15(2):205–214.
  • Greish K, Mathur A, Al Zahrani R, et al. Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer. J Control Release. 2018;291:184–195.
  • Fraguas-Sánchez AI, Torres-Suárez AI, Cohen M, et al. PLGA nanoparticles for the intraperitoneal administration of CBD in the treatment of ovarian cancer: in vitro and in ovo assessment. Pharmaceutics. 2020;12(5):439.
  • Lodzki M, Godin B, Rakou L, et al. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release. 2003;93(3):377–387.
  • Singh P, Pandit S, Garnaes J, et al. Green synthesis of gold and silver nanoparticles from cannabis sativa (industrial hemp) and their capacity for biofilm inhibition. IJN. 2018;13:3571–3591.
  • Esposito E, Drechsler M, Cortesi R, et al. Encapsulation of cannabinoid drugs in nanostructured lipid carriers. Eur J Pharm Biopharm. 2016;102:87–91.
  • Imran M, Iqubal MK, Ahmad S, et al. Stability-indicating high-performance thin-layer chromatographic method for the simultaneous determination of quercetin and resveratrol in the lipid-based nanoformulation. J Planar Chromatogr. 2019;32(5):393–400.
  • Modi D, Nirmal J, Warsi MH, et al. Formulation and development of tacrolimus-gellan gum nanoformulation for treatment of dry eye disease. Colloids Surf B Biointerfaces. 2022;211:112255.
  • Khan UA, Parveen U, Hasan N, et al. Parenteral sustained release lipid phase-transition system of ziprasidone: fabrication and evaluation for schizophrenia therapy. DDDT. 2020;14:2237–2247.
  • Bruni N, Della Pepa C, Oliaro-Bosso S, et al. Cannabinoid delivery systems for pain and inflammation treatment. Molecules. 2018;23(10):2478.
  • Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. Prog Polym Sci. 2014;39(2):268–307.
  • Devane WA, Hanuš L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949.
  • Bisogno T, Melck D, Bobrov MY, et al. N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J. 2000;351(3):817–824.
  • Porter AC, Sauer JM, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther. 2002;301(3):1020–1024.
  • Pagano G, Shyamsunder P, Verma RS, et al. Damaged mitochondria in Fanconi anemia – an isolated event or a general phenomenon? Oncoscience. 2014;1(4):287–295.
  • Zheng D, Bode AM, Zhao Q, et al. The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. Cancer Res. 2008;68(10):3992–3998.
  • Pérez-Gómez E, Andradas C, Blasco-Benito S, et al. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. J Natl Cancer Inst. 2015;107(6):djv077.
  • Joosten M, Valk PJM, Jordà MA, et al. Leukemic predisposition of pSca-1/Cb2 transgenic mice. Exp Hematol. 2002;30(2):142–149.
  • Nomura DK, Long JZ, Niessen S, et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140(1):49–61.
  • Thors L, Bergh A, Persson E, et al. Fatty acid amide hydrolase in prostate cancer: Association with disease severity and outcome, CB1 receptor expression and regulation by IL-4. PLOS One. 2010;5(8):e12275.
  • Wang D, Wang H, Ning W, et al. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res. 2008;68(15):6468–6476.
  • Izzo AA, Aviello G, Petrosino S, et al. Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med. 2008;86(1):89–98.
  • Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599–1608.
  • Munson AE, Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids. J Natl Cancer Inst. 1975;55(3):597–602.
  • Javid FA, Phillips RM, Afshinjavid S, et al. Cannabinoid pharmacology in cancer research: a new hope for cancer patients? Eur J Pharmacol. 2016;775:1–14.
  • Śledziński P, Zeyland J, Słomski R, et al. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med. 2018;7(3):765–775.
  • Hart S, Fischer OM, Ullrich A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res. 2004;64(6):1943–1950.
  • Zhu LX, Sharma S, Stolina M, et al. Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol. 2000;165(1):373–380.
  • McKallip RJ, Nagarkatti M, Nagarkatti PS. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol. 2005;174(6):3281–3289.
  • Del Pulgar TG, Velasco G, Sánchez C, et al. De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J. 2002;363(Pt 1):183–188.
  • Massi P, Valenti M, Vaccani A, et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem. 2008;104(4):1091–1100.
  • Singer E, Judkins J, Salomonis N, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015;6(1):e1601.
  • McAllister SD, Murase R, Christian RT, et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. 2011;129(1):37–47.
  • Nithipatikom K, Endsley MP, Isbell MA, et al. 2-Arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion. Cancer Res. 2004;64(24):8826–8830.
  • Soroceanu L, Murase R, Limbad C, et al. Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res. 2013;73(5):1559–1569.
  • McAllister SD, Christian RT, Horowitz MP, et al. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther. 2007;6(11):2921–2927.
  • Murase R, Kawamura R, Singer E, et al. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Br J Pharmacol. 2014;171(19):4464–4477.
  • Laezza C, Pisanti S, Crescenzi E, et al. Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells. FEBS Lett. 2006;580(26):6076–6082.
  • Wilkie G, Sakr B, Rizack T. Medical marijuana use in oncology. JAMA Oncol. 2016;2(5):670.
  • Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015;97(6):575–586.
  • Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239–257.
  • RA, Mattia C Ferrari A. Topical lidocaine: a new possible approach for localized neuropathic pain. Neuromodulation. 2014.
  • 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 USA. 1995;92(8):3376–3380.
  • Noyes R, Brunk SF, Avery DH, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975;18(1):84–89.
  • Noyes R, Brunk SF, Baram DA, et al. Analgesic effect of delta‐9‐tetrahydrocannabinol. J Clin Pharmacol. 1975;18(1):84–89.
  • Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–449.
  • Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010;39(2):167–179.
  • Khanna K, Sharma N, Rawat S, et al. Bhatnagar, intranasal solid lipid nanoparticles for management of pain: a full factorial design approach, characterization & gamma scintigraphy. Chem Phys Lipids. 2021;236:105060.
  • Hasan N, Imran M, Kesharwani P, et al. Intranasal delivery of naloxone-loaded solid lipid nanoparticles as a promising simple and non-invasive approach for the management of opioid overdose. Int J Pharm. 2021;599:120428.
  • Imran M, Iqubal MK, Imtiyaz K, et al. Topical nanostructured lipid carrier gel of quercetin and resveratrol: formulation, optimization, in vitro and ex vivo study for the treatment of skin cancer. Int J Pharm. 2020;587:119705.
  • Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. 2013;4(4):e0022.
  • Mokhtari RB, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022–38043.
  • Imran M, Saleem S, Chaudhuri A, et al. Docetaxel: an update on its molecular mechanisms, therapeutic trajectory and nanotechnology in the treatment of breast, lung and prostate cancer. J Drug Deliv Sci Technol. 2020;60:101959.
  • Atsmon J, Cherniakov I, Izgelov D, et al. PTL401, a new formulation based on pro-nano dispersion technology, improves oral cannabinoids bioavailability in healthy volunteers. J Pharm Sci. 2018;107(5):1423–1429.
  • Aparicio-Blanco J, Sebastián V, Benoit JP, et al. Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: in vitro screening of critical parameters. Eur J Pharm Biopharm. 2019;134:126–137.
  • Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studies. J Control Release. 2018;270:89–100.
  • Yin J, Xiang C, Wang P, et al. Biocompatible nanoemulsions based on hemp oil and less surfactants for oral delivery of baicalein with enhanced bioavailability. IJN. 2017;12:2923–2931.
  • Onaivi ES, Singh Chauhan BP, Sharma V. Challenges of cannabinoid delivery: how can nanomedicine help ? Nanomedicine. 2020;15(21):2023–2028.
  • Wang L, Mori W, Cheng R, et al. Synthesis and preclinical evaluation of sulfonamido-based [(11)C-Carbonyl]-carbamates and ureas for imaging monoacylglycerol lipase. Theranostics. 2016;6(8):1145–1159.
  • Mokoena DR, George BP, Abrahamse H. Enhancing breast cancer treatment using a combination of cannabidiol and gold nanoparticles for photodynamic therapy. IJMS. 2019;20(19):4771.
  • Grimsey NL, Savinainen JR, Attili B, et al. Regulating membrane lipid levels at the synapse by small-molecule inhibitors of monoacylglycerol lipase: new developments in therapeutic and PET imaging applications. Drug Discov Today. 2020;25(2):330–343.
  • Leghissa A, Hildenbrand ZL, Schug KA. The imperatives and challenges of analyzing cannabis edibles. Curr Opin Food Sci. 2019;28:18–24.
  • Chang Y, Zheng C, Chinnathambi A, et al. Properties of gold nanoparticles green-synthesized using Cannabis sativa L leaf aqueous extract. Arab. J. Chem. 2021;14(4):103060.
  • El-Hammadi MM, Small-Howard AL, Fernández-Arévalo M, et al. Industrial crops & products development of enhanced drug delivery vehicles for three cannabis-based terpenes using poly (lactic-co-glycolic acid) based nanoparticles. Ind Crops Prod. 2021;164:113345.
  • Patel N, Kommineni N, Kumar S, et al. Cannabidiol loaded extracellular vesicles sensitize triple-negative breast cancer to doxorubicin in both in-vitro and in vivo models. Int J Pharm. 2021;607:120943.
  • Console-Bram L, Brailoiu E, Brailoiu GC, et al. Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. Br J Pharmacol. 2014;171(16):3908–3917.
  • Patent.pdf; n.d.
  • Durán-Lobato M, Martín-Banderas L, Lopes R, et al. Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility. Drug Dev Ind Pharm. 2016;42(2):190–198.
  • Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today. 2003;8(24):1112–1120.
  • Siissalo S, De Waard H, De Jager MH, et al. Nanoparticle formulation of a poorly soluble cannabinoid receptor 1 antagonist improves absorption by rat and human intestine. Drug Metab Dispos. 2013;41(8):1557–1565.
  • Lung cancer – non-small cell: statistics. Cancer.Net; n.d.
  • Lung Cancer Statistics. How common is lung cancer?; n.d.
  • Ramer R, Heinemann K, Merkord J, et al. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013;12(1):69–82.
  • Ramer R, Rohde A, Merkord J, et al. Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm Res. 2010;27(10):2162–2174.
  • Ramer R, Bublitz K, Freimuth N, et al. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J. 2012;26(4):1535–1548.
  • Guindon J, Hohmann AG. The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol. 2011;163(7):1447–1463.
  • Sarfaraz S, Afaq F, Adhami VM, et al. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005;65(5):1635–1641.
  • Mimeault M, Pommery N, Wattez N, et al. Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate. 2003;56(1):1–12.
  • Sánchez MG, Sánchez AM, Ruiz-Llorente L, et al. Enhancement of androgen receptor expression induced by (R)-methanandamide in prostate LNCaP cells. FEBS Lett. 2003;555(3):561–566.
  • Ruiz L, Miguel A, Dı́az-Laviada I. Δ9-Tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett. 1999;458(3):400–404.
  • Sharma M, Hudson JB, Adomat H, et al. In vitro anticancer activity of plant-derived cannabidiol on prostate cancer cell lines. Pharmacol Pharmacy. 2014;5(8):806–820.
  • Ocaña A, Pandiella A. Identifying breast cancer druggable oncogenic alterations: lessons learned and future targeted options. Clin Cancer Res. 2008;14(4):961–970.
  • Tan JMY, Ng EYK, Acharya UR, et al. Comparative study on the use of analytical software to identify the different stages of breast cancer using discrete temperature data. J Med Syst. 2009;33(2):141–153.
  • Ban KA, Godellas CV. Epidemiology of breast cancer. Surg Oncol Clin N Am. 2014;23(3):409–422.
  • Vrechi TAM, Leão AHFF, Morais IBM, et al. Cannabidiol induces autophagy via ERK1/2 activation in neural cells. Sci Rep. 2021;11(1):5434.
  • De Petrocellis L, Melck D, Palmisano A, et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci USA. 1998;95(14):8375–8380.
  • Melck D, Rueda D, Galve-Roperh I, et al. Involvement of the cAMP/protein kinase a pathway and of mitogen- activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett. 1999;463(3):235–240.
  • Melck D, De Petrocellis L, Orlando P, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology. 2000;141(1):118–126.
  • Caffarel MM, Sarrió D, Palacios J, et al. Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 2006;66(13):6615–6621.
  • Grimaldi C, Pisanti S, Laezza C, et al. Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res. 2006;312(4):363–373.
  • Hernán Pérez de la Ossa D, Lorente M, Gil-Alegre ME, et al. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. PLOS One. 2013;8(1):e54795.
  • Nabissi M, Morelli MB, Santoni M, et al. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013;34(1):48–57.
  • Scott KA, Dalgleish AG, Liu WM. The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther. 2014;13(12):2955–2967.
  • Ivanov VN, Wu J, Hei TK. Oncotarget 74068 www.impactjournals.com/oncotarget regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways. Oncotarget. 2017;8(43):74068–74095.
  • Kosgodage US, Uysal-Onganer P, MacLatchy A, et al. Cannabidiol affects extracellular vesicle release, miR21 and miR126, and reduces prohibitin protein in glioblastoma multiforme cells. Transl Oncol. 2019;12(3):513–522.
  • Massi P, Vaccani A, Bianchessi S, et al. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. 2006;63(17):2057–2066.
  • Van Sickle MD, Duncan M, Kingsley PJ, et al. Neuroscience: identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310(5746):329–332.
  • Carracedo A, Gironella M, Lorente M, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006;66(13):6748–6755.
  • Fogli S, Nieri P, Chicca A, et al. Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006;580(7):1733–1739.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
  • Blázquez C, Carracedo A, Barrado L, et al. Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J. 2006;20(14):2633–2635.
  • Soliman E, Da L, Van Dross R, et al. Cannabinoids as therapeutics for non-melanoma and melanoma skin cancer. J Dermatol Clin Res. 2016;4(2):1069.
  • Gandhi S, Vasisth G, Kapoor A. Systematic review of the potential role of cannabinoids as antiproliferative agents for urological cancers. Can Urol Assoc J. 2017;11(3–4):E138–E142.
  • Glodde N, Jakobs M, Bald T, et al. Differential role of cannabinoids in the pathogenesis of skin cancer. Life Sci. 2015;138:35–40.
  • Nakajima J, Nakae D, Yasukawa K. Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice. J Pharm Pharmacol. 2013;65(8):1223–1230.
  • Ladin DA, Soliman E, Griffin LT, et al. Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Front Pharmacol. 2016;7:361.
  • Martínez-Martínez E, Gómez I, Martín P, et al. Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival. Oncoscience. 2015;2(2):131–141.
  • Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014;35(12):2787–2797.
  • Vara D, Salazar M, Olea-Herrero N, et al. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ. 2011;18(7):1099–1111.
  • Bartosch C, Gomes B, Jerónimo C, et al. Endometrial carcinoma in Portugal: demographic, diagnostic and treatment changes in the last 5 decades. Int J Gynecol Pathol. 2015;34(2):159–168.
  • Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
  • Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet. 2005;366(9484):491–505.
  • Fonseca BM, Correia-da-Silva G, Teixeira NA. Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis. J Physiol Biochem. 2018;74(2):261–272.
  • Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016;388(10061):2783–2795.
  • Bifulco M, Laezza C, Valenti M, et al. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 2004;18(13):1606–1608.
  • Cannabics capsules as treatment to improve cancer related CACS in advanced cancer patients – full text view – ClinicalTrials.gov; n.d.
  • Study to compare the safety and tolerability of Sativex® in patients with cancer related pain – full text view – ClinicalTrials.gov; n.d.
  • Australian clinical trials; n.d.
  • Inhaled cannabinoids versus immediate-release oral opioids for the management of breakthrough cancer pain – full text view – ClinicalTrials.gov; n.d.
  • Marijuana for cancer pain – full text view – ClinicalTrials.gov; n.d.
  • An observational post-marketing safety registry of Sativex® – full text view – ClinicalTrials.gov; n.d.
  • Comparison of delta-8-THC to ondansetron in the prevention of acute nausea from moderately emetogenic chemotherapy – full text view – ClinicalTrials.gov; n.d.
  • Assessment of single doses of oral dexanabinol in healthy subjects – full text view – ClinicalTrials.gov; n.d.
  • A study of Sativex® for pain relief in patients with advanced malignancy – full text view – ClinicalTrials.gov; n.d.
  • Cannabis for cancer-related symptoms – full text view – ClinicalTrials.gov; n.d.
  • Outcomes mandate national integration with cannabis as medicine for prevention and treatment of COVID-19 – full text view – ClinicalTrials.gov; n.d.
  • Cannabis oil for pain effectiveness – full text view – ClinicalTrials.gov; n.d.
  • ANZCTR – registration; n.d.
  • Pd G, Rm G, Ge H, et al. An open-label pilot study testing the feasibility of assessing total symptom burden in trials of cannabinoid medications in palliative care. J Palliat Med. 2020;23:650–655.
  • Long term safety of Sativex oromucosal spray (Sativex®; Nabiximols) as adjunctive therapy in patients with uncontrolled persistent chronic cancer related pain – full text view – ClinicalTrials.gov; n.d.
  • EUCTR2009-016065-29-GB, study of Sativex for the treatment of cancer related pain; n.d. Available from: http://www.who.int/Trialsearch/Trial2.Aspx?TrialID=EUCTR2009-016065-29-GB.
  • EudraCT Number 2009-016064-36 – clinical trial results – EU Clinical Trials Register; n.d.
  • GWCA1103 – study of Sativex for the treatment of cancer related pain – Health Research Authority; n.d.
  • Goyal S, Kubendran S, Kogan M, et al. High expectations: the landscape of clinical trials of medical marijuana in oncology. Complement Ther Med. 2020;49:102336.
  • A study of dexanabinol in combination with chemotherapy in patients with advanced tumours – full text view – ClinicalTrials.gov; n.d.
  • A study to assess the pharmacokinetic (PK) properties of Sativex® in patients with advanced cancer – full text view – ClinicalTrials.gov; n.d.
  • Safety and efficacy of smoked cannabis for improving quality of life in advanced cancer patients – full text view – ClinicalTrials.gov; n.d.
  • Orexigenic therapy with delta-9-tetrahydrocannabinol in advanced cancer patients with chemosensory abnormalities – a pilot study – full text view – ClinicalTrials.gov; n.d.
  • EUCTR2007-005225-30-IT, a double blind, randomized, placebo controlled, parallel group dose-range exploration study of Sativex in relieving pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy; n.d. Available from: http://www.who.int/Trialsearch/Trial2.Aspx?TrialID=EUCTR2007-005225-30-IT;.
  • A study: pure CBD as single-agent for solid tumor. Full text view – ClinicalTrials.gov; n.d.
  • A phase 1 study of dexanabinol in patients with advanced solid tumours – full text view – ClinicalTrials.gov; n.d.
  • Palonosetron and dexamethasone with or without dronabinol in preventing nausea and vomiting in patients receiving chemotherapy for cancer – full text view – ClinicalTrials.gov; n.d.
  • A safety study of Sativex compared with placebo (both with dose-intense temozolomide) in recurrent glioblastoma patients – full text view – ClinicalTrials.gov; n.d.
  • Tolerability of cannabis in patients receiving concurrent chemoradiation for glioblastoma – full text view – ClinicalTrials.gov; n.d.
  • TN-TC11G (THC+CBD) combination with temozolomide and radiotherapy in patients with newly-diagnosed glioblastoma – full text view – ClinicalTrials.gov; n.d.
  • A safety study of Sativex in combination with dose-intense temozolomide in patients with recurrent glioblastoma – full text view – ClinicalTrials.gov; n.d.
  • Dexanabinol in patients with brain cancer – full text view – ClinicalTrials.gov; n.d.
  • A pilot study of dronabinol for adult patients with primary gliomas – full text view – ClinicalTrials.gov; n.d.
  • A study of the efficacy of cannabidiol in patients with multiple myeloma, glioblastoma multiforme, and GI malignancies – full text view – ClinicalTrials.gov; n.d.
  • Cannabis oil and radiation therapy for the management of pain – full text view – ClinicalTrials.gov; n.d.
  • Pilot, Syndros, decreasing use of opioids in breast cancer subjects with bone mets – full text view – ClinicalTrials.gov; n.d.
  • EUCTR2017-000530-54-DK, the effect of cannabis on the appetite in cancer patients; n.d. Available from: http://www.who.int/Trialsearch/Trial2.Aspx?TrialID=EUCTR2017-000530-54-DK;.
  • The effect of cannabis in pancreatic cancer – full text view – ClinicalTrials.gov; n.d.
  • Investigation of cannabis for pain and inflammation in lung cancer – full text view – ClinicalTrials.gov; n.d.
  • Nabilone effect on the attenuation of anorexia, nutritional status and quality of life in lung cancer patients – full text view – ClinicalTrials.gov; n.d.
  • Cannabis use in cancer patients – full text view – ClinicalTrials.gov; n.d.
  • Medical cannabis during chemoradiation for head and neck cancer – full text view – ClinicalTrials.gov; n.d.
  • A pharmacokinetic study of single doses of Sativex in treatment-induced mucositis – full text view – ClinicalTrials.gov; n.d.
  • Clinical Trials Register – search for 2014-005553-39; n.d.
  • Evaluation prospectively the level of reduction in cognitive functions of cancer patients who are on active oncology treatments and use cannabis. The second goal is to identify high-risk groups for cognitive impairment due to cannabis use. Full text view; n.d.
  • Zylla DM, Eklund J, Gilmore G, et al. A randomized trial of medical cannabis in patients with stage IV cancers to assess feasibility, dose requirements, impact on pain and opioid use, safety, and overall patient satisfaction. Support Care Cancer. 2021;29(12):7471–7478.
  • Bar-Sela G, Cohen I, Campisi-Pinto S, et al. Cannabis consumption used by cancer patients during immunotherapy correlates with poor clinical outcome. Cancers. 2020;12(9):2447–2418.
  • Birnbaum AK, Karanam A, Marino SE, et al. Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia. 2019;60(8):1586–1592.
  • Hoffmann D, Brunnemann KD, Gori GB, et al. On the carcinogenicity of marijuana smoke. Recent Adv Phytochem. 1975:63–81.
  • Taylor FM. Marijuana as a potential respiratory tract carcinogen: a retrospective analysis of a community hospital population. South Med J. 1988;81(10):1213–1216.
  • Donald PJ. Marijuana smoking–possible cause of head and neck carcinoma in young patients. Otolaryngol Head Neck Surg. 1986;94:517–521.
  • Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA. 2015;313(24):2474–2483.
  • Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86–95.
  • Elsohly MA, Radwan MM, Gul W, et al. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017;103:1–36.
  • Wilkie G, Sakr B, Rizack T-J. Medical marijuana use in oncology: a review. JAMA Oncol. 2016;2:670–675.
  • Kaplan BLF, Springs AEB, Kaminski NE. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem Pharmacol. 2008;76:726–737.
  • Ca M, Eb R. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12–19.
  • Lachenmeier DW, Rehm J. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Sci Rep. 2015;5:8126.
  • Rong C, Carmona NE, Lee YL, et al. Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. Expert Opin Drug Saf. 2018;17(1):51–54.
  • Seamon MJ, Fass JA, Maniscalco-Feichtl M, et al. Medical marijuana medical marijuana and the developing role of the pharmacist. Am J Health Syst Pharm. 2007;64:1037–1044.
  • FDA. Highlights of prescribing information. These highlights do not include all the information needed to use EPIDIOLEX® safely and effectively. See full prescribing information for EPIDIOLEX. EPIDIOLEX® (cannabidi ol) oral solution, CX [pending DEA schedulin]; n.d.
  • CESAMET™ (nabilone) capsules; n.d.
  • Cannabis-based medicinal products NICE guideline; 2019.
  • Sativex oromucosal spray – summary of product characteristics (SmPC) – print friendly – (EMC); n.d.
  • FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. FDA; n.d.
  • Epidiolex (CBD) in patients with biochemically recurrent prostate cancer – full text view – ClinicalTrials.gov; n.d.
  • Solinas M, Massi P, Cinquina V, et al. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PLoS One. 2013;8(10):e76918.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.