schizophrenia and cannabis use have been linked for a long time in the scientific literature with three main hypothesis trying to explain this relationship (Gage et al., 2015).
The first hypothesis supports the idea of cannabis as a factor for schizophrenia development in subjects with genetic vulnerability for the disease (Caspi and Moffitt, 2006; Caspi et al., 2005; Gleason et al., 2012; Henquet et al., 2006; O’Tuathaigh et al., 2010).
Studies have shown that cannabis use can lead to psychotic symptoms and its use during adolescence has also been related to psychotic disorder development (Bossong and Niesink, 2010; Le Bec et al., 2009; Rehman and Farooq, 2007).
Frequency of cannabis use is also considered one of the factors of schizophrenia development and is related to an early age of onset of the disease on high frequency use (Compton et al., 2009; Henquet et al., 2005). Note that since cannabis use does not affect disease rate in a population level, there is no evidence to say that cannabis is the cause of schizophrenia in healthy subjects (Hill, 2015). The second hypothesis supports the idea of schizophrenia being one of the causes to use cannabis.
Cannabis would be used as self-medication in schizophrenia patients, probably due to the antipsychotic effects of cannabidiol and tetrahydrocannabivarin (Arnold et al., 2012; Cascio et al., 2015; Zuardi et al., 2012, 2006).
The third hypothesis focuses on the possibility of shared comorbidity between schizophrenia and cannabis use, either this comorbidity is genetic, environmental or mixed (French et al., 2015; Giordano et al., 2014; Verweij et al., 2017; Power et al., 2014).
Regarding the molecular mechanisms of the comorbidity between cannabis and schizophrenia, the endocannabinoid system has been related to schizophrenia. DAGL and NAPE are downregulated while MAGL and FAAH are upregulated in subjects who had a first episode of Psychosis (Bioque et al., 2013). endocannabinoids like Anandamide and 2-AG play an important role on Psychosis (Manseau and Goff, 2015). Some studies point to an Anandamide imbalance associated to Psychosis (Leweke, 2012). In unmedicated patients with acute Psychosis one of the body’s main endocannabinoids, Anandamide, is elevated 8-fold.
This elevation is absent in patients on anti-psychotics and is inversely correlated with psychotic symptoms, suggesting Anandamide actually functions to suppress psychotic behavior (Giuffrida et al., 2004). There is controversy regarding the role of the endocannabinoid receptor CB1 density, with studies showing lower density in schizophrenia patients than in controls and vice versa. CB1 density could also be affected by antipsychotic treatment (Dean et al., 2001; Ranganathan et al., 2015). PPAR-γ receptor has also been related to schizophrenia (Costa et al., 2013; Liu et al., 2014). 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.
These effects of CBD would point to the hypothesis of self-medication as the cause of cannabis use in schizophrenia subjects (Arnold et al., 2012; Bossong et al., 2014; Iseger and Bossong, 2015; Martin-Santos et al., 2012; Silva et al., 2015). In an animal study, THCV was found to have anti-psychotic effects through activation of the 5-HT1a receptor (Cascio et al., 2014). CBD acts as inverse agonist in CB1 receptor and THCV acts as an antagonist of CB1 receptor. These properties would counteract the psychotic symptoms of THC (Iseger and Bossong, 2015; Pertwee, 2005). Also, activated microglia are present in schizophrenia patients within the first 5 years of disease onset (van Berckel et al., 2008). Effects of CBD on activated microglia through PPAR-γ receptor could have also a role in schizophrenia.
Arnold, J.C., Boucher, A.A., and Karl, T. (2012). The yin and yang of cannabis-induced Psychosis: the actions of Delta(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia. Curr Pharm Des 18, 5113–5130.
van Berckel, B.N., Bossong, M.G., Boellaard, R., Kloet, R., Schuitemaker, A., Caspers, E., Luurtsema, G., Windhorst, A.D., Cahn, W., Lammertsma, A.A., et al. (2008). Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol. Psychiatry 64, 820–822.
Bioque, M., García-Bueno, B., Macdowell, K. S., Meseguer, A., Saiz, P. A., Parellada, M., … FLAMM-PEPs study—Centro de Investigacio´n Biome´dica en Red de Salud Mental. (2013). Peripheral endocannabinoid system dysregulation in first-episode Psychosis. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38(13), 2568-2577. https://doi.org/10.1038/npp.2013.165
Bossong, M.G., and Niesink, R.J.M. (2010). Adolescent brain maturation, the endogenous Cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog. Neurobiol. 92, 370–385.
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.
Cascio, M.G., Zamberletti, E., Marini, P., Parolaro, D., and Pertwee, R.G. (2015). The phytoCannabinoid, Δ 9 -tetrahydrocannabivarin, can act through 5-HT 1 A receptors to produce antipsychotic effects. Br. J. Pharmacol. 172, 1305–1318.
Caspi, A., and Moffitt, T.E. (2006). Gene–environment interactions in psychiatry: joining forces with neuroscience. Nat. Rev. Neurosci. 7, 583–590.
Caspi, A., Moffitt, T.E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., et al. (2005). Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction. Biol. Psychiatry 57, 1117–1127.
Compton, M.T., Kelley, M.E., Ramsay, C.E., Pringle, M., Goulding, S.M., Esterberg, M.L., Stewart, T., and Walker, E.F. (2009). Association of Pre-Onset Cannabis, Alcohol, and Tobacco Use With Age at Onset of Prodrome and Age at Onset of Psychosis in First-Episode Patients. Am. J. Psychiatry 166, 1251–1257.
Costa, M., Squassina, A., Congiu, D., Chillotti, C., Niola, P., Galderisi, S., Pistis, M., and Del Zompo, M. (2013). Investigation of endocannabinoid system genes suggests association between peroxisome proliferator activator receptor-α gene (PPARA) and schizophrenia. Eur. Neuropsychopharmacol. 23, 749–759.
Dean, B., Sundram, S., Bradbury, R., Scarr, E., and Copolov, D. (2001). Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of Cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103, 9–15.
French, L., Gray, C., Leonard, G., Perron, M., Pike, G.B., Richer, L., Séguin, J.R., Veillette, S., Evans, C.J., Artiges, E., et al. (2015). Early Cannabis Use, Polygenic Risk Score for schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry 72, 1002–1011.
Gage, S.H., Hickman, M., and Zammit, S. (2015). Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biol. Psychiatry.
Giordano, G.N., Ohlsson, H., Sundquist, K., Sundquist, J., and Kendler, K.S. (2014). The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study. Psychol. Med. 45, 407–414.
Giuffrida, A., Leweke, F.M., Gerth, C.W., Schreiber, D., Koethe, D., Faulhaber, J., Klosterkötter, J., and Piomelli, D. (2004). Cerebrospinal Anandamide Levels are Elevated in Acute schizophrenia and are Inversely Correlated with Psychotic Symptoms. Neuropsychopharmacology 29, 2108–2114.
Gleason, K.A., Birnbaum, S.G., Shukla, A., and Ghose, S. (2012). Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia. Transl. Psychiatry 2, e199.
Henquet, C., Murray, R., Linszen, D., and van Os, J. (2005). The environment and schizophrenia: the role of cannabis use. Schizophr. Bull. 31, 608–612.
Henquet, C., Rosa, A., Krabbendam, L., Papiol, S., Faňanás, L., Drukker, M., Ramaekers, J.G., and van Os, J. (2006). An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition. Neuropsychopharmacology 31, 2748–2757.
Hill, M. (2015). Perspective: Be clear about the real risks. Nature 525, S14–S14. Iseger, T.A., and Bossong, M.G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr. Res. 162, 153–161.
Jiang, W. (2005). cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J. Clin. Invest. 115, 3104–3116.
Le Bec, P.-Y., Fatséas, M., Denis, C., Lavie, E., and Auriacombe, M. (2009). Cannabis et psychose : recherche d’un lien de causalité à partir d’une revue critique systématique de la littérature. L’Encéphale 35, 377–385.
Leweke, F.M. (2012). Anandamide dysfunction in prodromal and established Psychosis. Curr. Pharm. Des. 18, 5188–5193.
Liu, Y.-R., Hu, T.-M., Lan, T.-H., Chiu, H.-J., Chang, Y.-H., Chen, S.-F., Yu, Y.-H., Chen, C.-C., and Loh, E.-W. (2014). Association of the PPAR-γ Gene with Altered Glucose Levels and Psychosis Profile in schizophrenia Patients Exposed to Antipsychotics. Psychiatry Investig. 11, 179–185.
Manseau, M.W., and Goff, D.C. (2015). cannabinoids and schizophrenia: Risks and Therapeutic Potential. Neurotherapeutics 1–9.
Martin-Santos, R., Crippa, J.A., Batalla, A., Bhattacharyya, S., Atakan, Z., Borgwardt, S., Allen, P., Seal, M., Langohr, K., Farre, M., et al. (2012). Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers. CPD 18, 4966–4979.
O’Tuathaigh, C.M., Hryniewiecka, M., Behan, A., Tighe, O., Coughlan, C., Desbonnet, L., Cannon, M., Karayiorgou, M., Gogos, J.A., Cotter, D.R., et al. (2010). Chronic Adolescent Exposure to Δ-9-Tetrahydrocannabinol in COMT Mutant Mice: Impact on Psychosis-Related and Other Phenotypes. Neuropsychopharmacology 35, 2262–2273.
Pertwee, R.G. (2005). Pharmacological Actions of cannabinoids. In cannabinoids, P.D.R.G. Pertwee, ed. (Springer Berlin Heidelberg), pp. 1–51.
Power, R.A., Verweij, K.J.H., Zuhair, M., Montgomery, G.W., Henders, A.K., Heath, A.C., Madden, P.A.F., Medland, S.E., Wray, N.R., and Martin, N.G. (2014). Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol. Psychiatry 19, 1201–1204.
Ranganathan, M., Cortes-Briones, J., Radhakrishnan, R., Thurnauer, H., Planeta, B., Skosnik, P., Gao, H., Labaree, D., Neumeister, A., Pittman, B., et al. (2015). Reduced Brain Cannabinoid Receptor Availability In schizophrenia. Biol. Psychiatry.
Rehman, I.U., and Farooq, S. (2007). schizophrenia and comorbid self reported cannabis abuse: impact on course, functioning and services use. JPMA J. Pak. Med. Assoc. 57, 60–64.
Schwarcz, G., Karajgi, B., and McCarthy, R. (2009). Synthetic Δ-9-Tetrahydrocannabinol (Dronabinol) Can Improve the Symptoms of schizophrenia. J. Clin. Psychopharmacol. 29, 255–258.
Silva, T.B.G., Balbino, C.Q., and Weiber, A.F.M. (2015). The relationship between cannabidiol and Psychosis: A review. Ann. Clin. Psychiatry Off. J. Am. Acad. Clin. Psychiatr. 27, 134–141.
Verweij, K. J. H., Abdellaoui, A., Nivard, M. G., Cort, A. S., Ligthart, L., Draisma, H. H. M., … Vink, J. M. (2017). Short communication: Genetic association between schizophrenia and cannabis use. Drug & Alcohol Dependence, 171, 117-121. https://doi.org/10.1016/j.drugalcdep.2016.09.022
Zuardi, A., Alexandre S. Crippa, J., E.C. Hallak, J., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., K. McGuire, P., and Silveira Guimaraes, F. (2012). A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Translational Investigation. CPD 18, 5131–5140.
Zuardi, A.W., Crippa, J.A.S., Hallak, J.E.C., Moreira, F.A., and Guimarães, F.S. (2006). Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39, 421–429.