THC binds to CB1, CB2, TRPV2, TRPV3, TRPV4, TRPA1, TRM8, PPARγ, GlyR, GPR55, GPR18 and 5HT3A (Morales, Hurst, & Reggio, 2017).
In rhesus macaques, THC (0.32 mg/kg, twice daily, intramuscular) was found to significantly decrease viral load development and decrease mortality from Simian Immunodeficiency Virus (the monkey equivalent of Human Immunodeficiency Virus)(Molina et al., 2011). This protective effect is at least partially due to a THC-driven change in microRNA expression towards an anti-inflammatory profile (Chandra et al., 2014). Negative side effects of THC use (loss of memory, attention and motor function) were only transient. Thus it seems that the negative side effects of THC are transient while the therapeutic effects remain in the treatment of Immunodeficiency Viruses (Winsauer et al., 2011).
In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).
In a mouse model of Autism (BTBR T+tf/J mice), THC was found to alleviate aberrant locomotor behavior associated to Autism (Onaivi et al., 2011).
THC showed anti cancer properties in several studies through CB1 and CB2 receptors (Caffarel et al., 2008). For an excellent publicly available review on therapeutic cannabinoids in cancer please see: Chakravarti et al. (2014).
CB2 agonists as anandamide or THC affect the inflammatory process of bone cancer cells by modulating interleukin, tumor necrosis factor α and nuclear factor-κB expression and cofilin-1 protein (Hsu et al., 2007; Lu et al., 2015; Yang et al., 2015).
THC overexpress TIMP-1 with anti invasive and apoptotic functions on cancer cells (Ramer and Hinz, 2008).
Studies in THC and synthetic CB2 agonists shown downregulation of MMP-2, cell invasion and cell viability related to Glioblastoma (Blázquez et al., 2008; Galanti et al., 2008; Hernán Pérez de la Ossa et al., 2013). CBD improves effectiveness of THC and is also effective in Glioblastoma THC-resistant cells (Marcu et al., 2010; Solinas et al., 2013). The action of cannabinoids on Glioblastoma receptors produces an antitumoral response against cancer cell growth, migration, angiogenesis and proliferation (Moreno et al., 2014). However, this response does not affect non-tumor cells, making cannabinoids a safe cancer treatment (Rocha et al., 2014). In glioma xenografts 7.5 mg/kg/day CBD decreased tumor growth by about 20%. 7.5 mg/kg/day THC produced similar results and combined application of CBD and THC reduced tumor growth by approximately 50% suggesting synergy between both pathways (Torres et al., 2011). In mice a combination of CBD and THC was found to work synergistically with radiation therapy to reduce tumor size (Scott et al., 2014).
Studies with THC shown cytotoxic properties induced by apoptosis in Leukemia cells (Herrera et al., 2005; Jia et al., 2006; Liu et al., 2008).
In cancer cell lines (A549 and H460) and human metastatic lung cancer cells CBD as well as THC promote ICAM-mediated Lymphokine-Activated Killer cell adhesion and cancer cell lysis (Haustein et al., 2014).
In one study, THC effectively killed pancreatic cancer cells (in Panc1, Capan2, BxPc2 and MIA PaCa-2 cell lines) at 2 μM and higher concentrations (Carracedo et al., 2006). The authors found that both CB1 and CB2 were upregulated in cancer cells. Apoptosis was CB2-dependent. In mice, 15 mg/kg/d THC induced tumor cell-specific apoptosis and significantly reduced tumor growth (Carracedo et al., 2006).
The six major plant cannabinoids, THC, CBD, CBC, CBG, CBDA and THCV were tested for their effect on bronchoconstriction, inflammation and coughing in guinea pigs. Only THC reduced all three parameters through activation of CB1 and CB2 receptors (Makwana et al., 2015).
In animal models for depression (forced swimming test, tail suspension test), Δ9THC showed anti-depressant properties at a dose of 2.5 mg/kg (El-Alfy et al., 2010).
THC was found to help maintain healthy blood-glucose levels and counteract diabetic oxidative stress (Coskun and Bolkent, 2014). THC showed immunosupressive effects reducing the incidence and slowing-down the development of type 1 Diabetes (Li et al., 2001).
Topical application of THC also suppresses skin inflammation, but in a CB1- and CB2-independent way (Gaffal et al., 2013). A comparative study into the topical anti-inflammatory activity of cannabinoids (on croton oil-inflamed skin in mice) showed that Δ8THC, Δ9THC and THCV are about half as effective in reducing inflammation as Indometacin (a commonly used Non-steroid anti-inflammatory drug), but approximately 5 times more effective than CBCV and CBD. CBC and CBDV had no appreciable anti-inflammatory activity (Tubaro et al., 2010).
THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011). In heterologous cells (HEK293), THC and CBD were found to inhibit T-type calcium channels with an IC50 of approximately 1μM (Ross et al., 2008). Preclinical studies shows that, in addition to CBD, CBDV and THC also have anti-convulsant properties (Hill et al., 2013; Wallace et al., 2001). In a mouse model of epilepsy (Maximal Electro Shock), the following cannabinoids were found to be anti-convulsive (ED50)(referenced within: Devinsky et al., 2014): CBD 120 mg/kg Δ9THC 100 mg/kg 11-OH-Δ9THC 14 mg/kg 8β-OH-Δ9THC 100 mg/kg Δ9THCA 200-400 mg/kg Δ8THC 80 mg/kg CBN 230 mg/kg Δ9α/β-OH-hexahydro-CBN 100 mg/kg Apart from that the doses reported above are incredibly high, it does provide a proof of principle that many cannabinoids exert anti-convulsive effects.
A sub-population of patients with fibromyalgia showed lower pain perception after daily administration of THC (2.5 to 15mg). Authors suggested these effects are due to the analgesic action of THC in the central nervous system (Schley et al., 2006)
Functional Gastro-Intestinal Disorders
Many Crohn’s disease patients self-administer cannabis suggesting a role for cannabinoids in the treatment of Crohn’s or in the alleviation of its symptoms. Although many patients reported symptomatic improvement of abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%) and diarrhea (28.6%), cannabis use was also associated with increased hospitalization (Storr et al., 2014). This could be explained as cannabis (or the vehicle it comes in, like tobacco) being harmful in Crohn’s. Alternatively, patients with more severe Crohn’s disease may be sooner inclined to use cannabis to alleviate the symptoms. In rats, intra-colonic application of 1 to 10 mg/kg cannabis extract dose-dependently reduced colitis severity but oral application did not (Wallace et al., 2013). This effect was independent of CB1 or CB2 receptors. However, oral extract did prevent NSAID-induced gastric damage at 10 mg/kg in a CB1-dependent way. Cannabis extract also reduced visceral pain at 3 mg/kg in a CB2-dependent way suggesting cannabis extract has distinct beneficial effects in gastro-intestinal disorders via CB1/2-dependent and independent pathways (Wallace et al., 2013). Interestingly, injection of 100 mg/kg THC produced strong diarrhea in CB1 deficient mice but not in controls suggesting complex involvement of CB1 in the regulation of intestinal transit (Zimmer et al., 1999).
Administration of THC in people with Insomnia showed decreased time to fall asleep compared to controls (Cousens and DiMascio, 1973). In a different study, administration of smoked cannabis containing THC also showed benefits to fall asleep and increased stage 4 sleep (Schierenbeck et al., 2008). Symptoms with higher reports of cannabis use are pain, Anxiety and Insomnia (Walsh et al., 2013). In two different studies, subjects with high scores of PTSD reported benefits of using cannabis to cope with PTSD-related Insomnia (Bonn-Miller et al., 2010, 2014). In a study focusing on sleep disorders and cannabis use, 81 participants reported use of cannabis to treat Insomnia and 14 participants reported use of cannabis to reduce nightmares (Belendiuk et al., 2015). A cannabinoid dependent study showed that subjects reported residual effects during daytime after the administration of THC before sleeping. CBD would eliminate those residual effects but subjects reported sleepiness after CBD administration (Nicholson et al., 2004). For more information, please read a review on the topic by Gates et al. (2014).
In rats, the after-effects of MDMA (2 x 10 mg/kg) include hyperthermia, increased Anxiety-like behavior and reduced exploration. Administration of THC reduced these behavioral effects. In addition, THC normalized serotonin levels and prevented MDMA-induced neurotoxicity (Shen et al., 2011)
In rats, THC dose dependently suppressed Cortical Spreading depression (CSD) amplitude, duration and propagation through CB1 but not CB2 activation (Kazemi et al., 2012).
Morphine shows enhanced potency when is combined with THC in animal models (Smith et al., 1998; Tham et al., 2005). This synergy effect is shown to be useful to avoid tolerance when both THC and Morphine are administered together in low doses (Cichewicz and McCarthy, 2003; Smith et al., 2007).
In a mouse model of MS (Theiler's murine encephalomyelitis), Sativex (50/50% THC/CBD oromucoso spray was compared with CBD-enriched or THC-enriched cannabis extract. Motor deterioration and inflammation (astrogliosis) were equally reduced by Sativex and CBD-enriched extract but THC-enriched extract was less effective. The effects of CBD were PPARγ-mediated whereas THC signaling was CB1/2 dependent (Feliú et al., 2015).
In mice, inhibition of opioid-degrading enzymes potentiates the analgesic effect of THC, suggesting cross talk or synergy between the opioid- and endocannabinoid systems in pain management (Reche et al., 1998). In humans, on the other hand, THC was found not so much to enhance the analgesic effect of morphine but to inhibit the experienced discomfort that is normally associated with pain (Roberts et al., 2006). In a rat model, THC was found to suppress muscle pain via activation of CB1 (Bagüés et al., 2014).
In human neuroblastoma cells, THC, but not CBD was found to be neuroprotective. Neuroprotection was mediated by PPARγ (Carroll et al., 2012). In animal models THC and CBD were neuroprotective via CB1 or CB2 receptors (Lastres-Becker et al., 2005). In cultured midbrain neurons, CBD, THCA and THC had anti-oxidative properties.Moreover, THCA and THC were shown to be neuroprotective (Moldzio et al., 2012). In a marmoset model of Parkinson’s THC improved locomotor activity (van Vliet et al., 2006).
THC, CBD, CBN and CBG were found to inhibit human keratinocyte (skin cell) proliferation suggesting therapeutic potential in Psoriasis (Wilkinson and Williamson, 2007). The effect of THC is at least partially dependent on CB1. Given its affinity for CB receptors, CBN is also likely to function through CB1/2. CBD and CBG do not function through classical CB receptors and none of the phytocannabinoids depended on TRPV1 for their effect (in contrast to endocannabinoid function below), but PPARγ and GPR55 may be involved (Wilkinson and Williamson, 2007).
psychosis and Schizophrenia
CB1 receptor agonist THC has been reported to mimic psychotic symptoms in healthy volunteers, supporting the argument of a role of the endocannabinoid system in Schizophrenia (Bossong et al., 2014). Some studies suggest that THC is the responsible of the psychosis symptoms while CBD would act as antipsychotic and anxiolytic.
Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843.
Bagüés, A., Martín, M.I., and Sánchez-Robles, E.M. (2014). Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. Eur. J. Pharmacol. 745C, 69–75.
Belendiuk, K.A., Babson, K.A., Vandrey, R., and Bonn-Miller, M.O. (2015). Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181.
Blázquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., Haro, A., Velasco, G., and Guzmán, M. (2008). cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. cancer Res. 68, 1945–1952.
Bonn-Miller, M.O., Babson, K.A., Vujanovic, A.A., and Feldner, M.T. (2010). Sleep Problems and PTSD Symptoms Interact to Predict Marijuana Use Coping Motives: A Preliminary Investigation. J. Dual Diagn. 6, 111–122.
Bonn-Miller, M.O., Babson, K.A., and Vandrey, R. (2014). Using Cannabis To Help You Sleep: Heightened Frequency of Medical Cannabis Use among Those with PTSD. Drug Alcohol Depend. 136, 162–165.
Bossong, M.G., Jansma, J.M., Bhattacharyya, S., and Ramsey, N.F. (2014). Role of the endocannabinoid system in brain functions relevant for Schizophrenia: an overview of human challenge studies with cannabis or 9-tetrahydrocannabinol (THC). Prog Neuropsychopharmacol Biol Psychiatry 52, 53–69.
Caffarel, M.M., Moreno-Bueno, G., Cerutti, C., Palacios, J., Guzman, M., Mechta-Grigoriou, F., and Sanchez, C. (2008). JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27, 5033–5044.
Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., and Iovanna, J.L. (2006). cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. cancer Res. 66, 6748–6755.
Carroll, C.B., Zeissler, M.-L., Hanemann, C.O., and Zajicek, J.P. (2012). Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol. Appl. Neurobiol. 38, 535–547.
Chakravarti, B., Ravi, J., and Ganju, R.K. (2014). cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 5, 5852–5872.
Chandra, L.C., Kumar, V., Torben, W., Stouwe, C.V., Winsauer, P., Amedee, A., Molina, P.E., and Mohan, M. (2014).Chronic administration of Δ9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute SIV infection of rhesus macaques.
Cichewicz, D.L., and McCarthy, E.A. (2003). Antinociceptive Synergy between Δ9-Tetrahydrocannabinol and Opioids after Oral Administration. J. Pharmacol. Exp. Ther. 304, 1010–1015.
Cousens, K., and DiMascio, A. (1973). (−)δ9 THC as an hypnotic. Psychopharmacologia 33, 355–364. Gates, P.J., Albertella, L., and Copeland, J. (2014). The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med. Rev. 18, 477–487.
Coskun, Z.M., and Bolkent, S. (2014). Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ9-THC. Cell Biochem. Funct. 32, 612–619.
Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W.G., et al. (2014). Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791–802.
Feliú, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernández-Ruiz, J., and Guaza, C. (2015). A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.
Gaffal, E., Cron, M., Glodde, N., and Tüting, T. (2013). Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy 68, 994–1000.
Galanti, G., Fisher, T., Kventsel, I., Shoham, J., Gallily, R., Mechoulam, R., Lavie, G., Amariglio, N., Rechavi, G., and Toren, A. (2008). Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human Glioblastoma multiforme cells. Acta Oncol. Stockh. Swed. 47, 1062–1070.
Gates, P.J., Albertella, L., and Copeland, J. (2014). The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med. Rev. 18, 477–487.
Goonawardena, A.V., Riedel, G., and Hampson, R.E. (2011). cannabinoids alter spontaneous firing, bursting, and cell synchrony of hippocampal principal cells. Hippocampus 21, 520–531.
El-Alfy, A.T., Ivey, K., Robinson, K., Ahmed, S., Radwan, M., Slade, D., Khan, I., ElSohly, M., and Ross, S. (2010). Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol. Biochem. Behav. 95, 434–442.
Haustein, M., Ramer, R., Linnebacher, M., Manda, K., & Hinz, B. (2014). cannabinoids increase Lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Biochemical Pharmacology, 92(2), 312-325. https://doi.org/10.1016/j.bcp.2014.07.014
Hernán Pérez de la Ossa, D., Lorente, M., Gil-Alegre, M.E., Torres, S., García-Taboada, E., Aberturas, M.D.R., Molpeceres, J., Velasco, G., and Torres-Suárez, A.I. (2013). Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of Glioblastoma multiforme. PloS One 8, e54795.
Herrera, B., Carracedo, A., Diez-Zaera, M., Guzmán, M., and Velasco, G. (2005). p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells. FEBS Lett. 579, 5084–5088.
Hill, T.D.M., Cascio, M.-G., Romano, B., Duncan, M., Pertwee, R.G., Williams, C.M., Whalley, B.J., and Hill, A.J. (2013). Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br. J. Pharmacol. 170, 679–692.
Hsu, S.-S., Huang, C.-J., Cheng, H.-H., Chou, C.-T., Lee, H.-Y., Wang, J.-L., Chen, I.-S., Liu, S.-I., Lu, Y.-C., Chang, H.-T., et al. (2007).Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 231, 21–29.
Jia, W., Hegde, V.L., Singh, N.P., Sisco, D., Grant, S., Nagarkatti, M., and Nagarkatti, P.S. (2006). Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat Leukemia T cells is regulated by translocation of Bad to mitochondria. Mol. cancer Res. MCR 4, 549–562.
Kazemi, H., Rahgozar, M., Speckmann, E.-J., and Gorji, A. (2012). Effect of cannabinoid receptor activation on spreading depression. Iran. J. Basic Med. Sci. 15, 926–936.
Lastres-Becker, I., Molina-Holgado, F., Ramos, J.A., Mechoulam, R., and Fernández-Ruiz, J. (2005). cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis. 19, 96–107.
Li, X., Kaminski, N.E., and Fischer, L.J. (2001). Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune Diabetes. Int. Immunopharmacol. 1, 699–712.
Liu, W.M., Scott, K.A., Shamash, J., Joel, S., and Powles, T.B. (2008). Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. Leuk. Lymphoma 49, 1800–1809.
Lu, C., Liu, Y., Sun, B., Sun, Y., Hou, B., Zhang, Y., Ma, Z., and Gu, X. (2015).Intrathecal Injection of JWH-015 Attenuates bone cancer pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord. Inflammation.
Makwana, R., Venkatasamy, R., Spina, D., and Page, C. (2015). The effect of phytocannabinoids on airway hyperresponsiveness, airway inflammation and cough. J. Pharmacol. Exp. Ther.
Marcu, J.P., Christian, R.T., Lau, D., Zielinski, A.J., Horowitz, M.P., Lee, J., Pakdel, A., Allison, J., Limbad, C., Moore, D.H., et al. (2010). Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human Glioblastoma cell proliferation and survival. Mol. cancer Ther. 9, 180–189
Massi, P., Solinas, M., Cinquina, V., and Parolaro, D. (2013). Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 75, 303–312.
Moldzio, R., Pacher, T., Krewenka, C., Kranner, B., Novak, J., Duvigneau, J.C., and Rausch, W.-D. (2012). Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine Int. J. Phytother. Phytopharm. 19, 819–824.
Molina, P.E., Winsauer, P., Zhang, P., Walker, E., Birke, L., Amedee, A., Stouwe, C.V., Troxclair, D., McGoey, R., Varner, K., et al. (2011).cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res. Hum. Retroviruses 27, 585–592.
Morales, P., Hurst, D. P., & Reggio, P. H. (2017). Molecular Targets of the Phytocannabinoids-A Complex Picture. Progress in the chemistry of organic natural products, 103, 103-131. https://doi.org/10.1007/978-3-319-45541-9_4
Moreno, E., Andradas, C., Medrano, M., Caffarel, M.M., Pérez-Gómez, E., Blasco-Benito, S., Gómez-Cañas, M., Pazos, M.R., Irving, A.J., Lluís, C., et al. (2014). Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J. Biol. Chem. 289, 21960–21972.
Nicholson, A.N., Turner, C., Stone, B.M., and Robson, P.J. (2004). Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J. Clin. Psychopharmacol. 24, 305–313.
Onaivi, E.S., Benno, R., Halpern, T., Mehanovic, M., Schanz, N., Sanders, C., Yan, X., Ishiguro, H., Liu, Q.-R., Berzal, A.L., et al. (2011). Consequences of cannabinoid and monoaminergic system disruption in a mouse model of Autism spectrum disorders. Curr. Neuropharmacol. 9, 209–214.
Ramer, R., and Hinz, B. (2008). Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J. Natl. cancer Inst. 100, 59–69.
Roberts, J.D., Gennings, C., and Shih, M. (2006). Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530, 54–58.
Rocha, F.C.M., Santos Júnior, J.G. Dos, Stefano, S.C., and da Silveira, D.X. (2014). Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J. Neurooncol. 116, 11–24.
Ross, H.R., Napier, I., and Connor, M. (2008). Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J. Biol. Chem. 283, 16124–16134.
Schierenbeck, T., Riemann, D., Berger, M., and Hornyak, M. (2008). Effect of illicit recreational drugs upon sleep: cocaine, ecstasy and marijuana. Sleep Med. Rev. 12, 381–389.
Schley, M., Legler, A., Skopp, G., Schmelz, M., Konrad, C., & Rukwied, R. (2006). Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Current Medical Research and Opinion, 22(7), 1269-1276. https://doi.org/10.1185/030079906X112651
Scott, K.A., Dalgleish, A.G., and Liu, W.M. (2014). The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Mol. cancer Ther.
Shen, E.Y., Ali, S.F., and Meyer, J.S. (2011). Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats. Neuropharmacology 61, 1183–1192.
Smith, F.L., Cichewicz, D., Martin, Z.L., and Welch, S.P. (1998). The Enhancement of Morphine Antinociception in Mice by Δ9-Tetrahydrocannabinol. Pharmacol. Biochem. Behav. 60, 559–566.
Smith, P.A., Selley, D.E., Sim-Selley, L.J., and Welch, S.P. (2007). Low dose combination of Morphine and Δ9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur. J. Pharmacol. 571, 129–137.
Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., and Parolaro, D. (2013). Cannabidiol, a Non-Psychoactive cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect. PLoS ONE 8.
Storr, M., Devlin, S., Kaplan, G.G., Panaccione, R., and Andrews, C.N. (2014). Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm. Bowel Dis. 20, 472–480.
Tham, S.M., Angus, J.A., Tudor, E.M., and Wright, C.E. (2005). Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2-adrenoceptor agonists in acute pain models in mice. Br. J. Pharmacol. 144, 875–884.
Torres, S., Lorente, M., Rodríguez-Fornés, F., Hernández-Tiedra, S., Salazar, M., García-Taboada, E., Barcia, J., Guzmán, M., and Velasco, G. (2011). A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. cancer Ther. 10, 90–103.
Tubaro, A., Giangaspero, A., Sosa, S., Negri, R., Grassi, G., Casano, S., Della Loggia, R., and Appendino, G. (2010). Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 81, 816–819.
van Vliet, S.A.M., Vanwersch, R.A.P., Jongsma, M.J., van der Gugten, J., Olivier, B., and Philippens, I.H.C.H.M. (2006). Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects. Behav. Pharmacol. 17, 453–462.
Wallace, J.L., Flannigan, K.L., McKnight, W., Wang, L., Ferraz, J.G.P., and Tuitt, D. (2013). Pro-resolution, protective and anti-nociceptive effects of a cannabis extract in the rat gastrointestinal tract. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 64, 167–175.
Wallace, M.J., Wiley, J.L., Martin, B.R., and DeLorenzo, R.J. (2001). Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur. J. Pharmacol. 428, 51–57.
Walsh, Z., Callaway, R., Belle-Isle, L., Capler, R., Kay, R., Lucas, P., and Holtzman, S. (2013). Cannabis for therapeutic purposes: Patient characteristics, access, and reasons for use. Int. J. Drug Policy 24, 511–516
Wilkinson, J.D., and Williamson, E.M. (2007). cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of Psoriasis. J. Dermatol. Sci. 45, 87–92.
Winsauer, P.J., Molina, P.E., Amedee, A.M., Filipeanu, C.M., McGoey, R.R., Troxclair, D.A., Walker, E.M., Birke, L.L., Stouwe, C.V., Howard, J.M., et al. (2011).Tolerance to chronic delta-9-tetrahydrocannabinol (Δ9-THC) in rhesus macaques infected with simian immunodeficiency virus. Exp. Clin. Psychopharmacol. 19, 154–172.
Yang, L., Li, F.-F., Han, Y.-C., Jia, B., and Ding, Y. (2015).cannabinoid receptor CB2 is involved in tetrahydrocannabinol-induced anti-inflammation against lipopolysaccharide in MG-63 cells. Mediators Inflamm. 2015, 362126.
Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M., and Bonner, T.I. (1999). Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. U. S. A. 96, 5780–5785.