Psychosis and cannabis use have been linked for a long time in the scientific literature. However, this relationship is not easy to understand due to the complexity of the disease itself and the existing limitations of the scientific methodology to study such a relationship. Cannabis has been proposed as the cause of Psychosis, but at the same time, Psychosis has been proposed as the cause of cannabis use. Also, the relationship between both traits could be bidirectional as suggested by Degenhardt et al. (2018). Currently, there are three main hypothesis trying to explain this relationship (Gage et al., 2015).
The first hypothesis supports the idea of cannabis being 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).
Shahzade et al. (2018) suggest that the type of use of cannabis in genetic vulnerable subjects to Psychosis could predict their disease outcome. 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 users (Arranz et al., 2018; Compton et al., 2009; Henquet et al., 2005; Mustonen et al., 2018). Gender could also moderate the relationship between cannabis use and the onset of Psychosis (Albertella et al., 2017; Setién-Suero et al., 2017)
Use of cannabis after the first episode of Psychosis has been related with a poorer prognosis of the disease (Shah et al., 2017)
Schizophrenia patients with high cannabis use before Schizophrenia onset showed higher predisposition to Schizophrenia than non users (Aas et al., 2018)
The use of cannabis before the onset of Schizophrenia has been associated with cortical thinning in the caudal middle frontal gyrus (Hartberg et al., 2018)
COMT Val158Met genotype could modulate the age of onset of Psychosis in cannabis users (Lodhi et al., 2017)
Patients with cannabis-induced psychotic disorders showed similar prepulse inhibition deficits when compared to patients with Schizophrenia and cannabis abuse (Morales-Muñoz et al., 2017)
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 of cannabis use. Cannabis would be used as self-medication in Schizophrenia patients, maybe due to the antipsychotic effects of CBD and THCV or maybe due to other mechanisms related to THC (Arnold et al., 2012; Cascio et al., 2015; Zuardi et al., 2012, 2006).
In fact, cannabis use (commonly high THC) could counteract some markers and/or cognitive deficits related to Schizophrenia, while it could also increase those in healthy controls (Rentzsch et al., 2017; Roser et al., 2018).
Schizophrenia has been previously related to impaired fronto-striatal connectivity. Oral administration of CBD (600 mg) showed improved connectivity of these areas (Grimm et al., 2018)
Cannabis use has been associated with lower reduction of total gray matter density compared to non users in a group of psychotic individuals (Abush et al., 2018).
Acute effects of cannabis use in cannabis users with high risk of Psychosis showed higher psychotic effects and lower neurocognitive performance than cannabis users with lower risk of Psychosis (Vadhan et al., 2017)
Moderate use of cannabis is related with lower cognitive impairment compared to low and high use of cannabis in a group of patients with Schizophrenia (Schnakenberg Martin et al., 2016)
Patients who show psychotic symptoms under the effects of cannabis need shorter interventions and/or hospitalizations than patients who did not use cannabis (Rylander et al., 2018)
However, a recent meta-analyses points in the opposite direction, showing worse cognitive functioning in patients with Schizophrenia who used cannabis compared to non-users (Bogaty et al., 2018)
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; Power et al., 2014). In fact, in the last study from Pasman et al. (2018), causality from cannabis use to Schizophrenia was tested with weak evidence, in contrast to the causality from Schizophrenia to cannabis use, which had stronger evidence, suggesting that subjects with Schizophrenia have higher chances to use cannabis.
Regarding the molecular mechanisms of the comorbidity between cannabis and Schizophrenia, the Endocannabinoid system has been already linked to the disease. endocannabinoids like Anandamide and 2-AG could play an important role on Psychosis (Manseau and Goff, 2015).
Cannabis use has been associated with low glutamate leves in the prefrontal cortex while this has been shown also in patients with Schizophrenia (Rigucci et al., 2018)
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).
Long term THC exposure can sensitize 5HT2A receptors, which are related to hallucinations linked to Schizophrenia and Psychosis (Ibarra-Lecue et al., 2018).
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).
Cannabis use has been associated with higher cortisol levels in patients with ultra high risk of Psychosis (Carol et al., 2017)
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.
Aas, M., Melle, I., Bettella, F., Djurovic, S., Hellard, S.L., Bjella, T., Ringen, P.A., Lagerberg, T.V., Smeland, O.B., Agartz, I., et al. (2018). Psychotic patients who used cannabis frequently before illness onset have higher genetic predisposition to Schizophrenia than those who did not. Psychol. Med. 48, 43–49.
Abush, H., Ghose, S., Van Enkevort, E.A., Clementz, B.A., Pearlson, G.D., Sweeney, J.A., Keshavan, M.S., Tamminga, C.A., and Ivleva, E.I. (2018). Associations between adolescent cannabis use and brain structure in Psychosis. Psychiatry Res. Neuroimaging 276, 53–64.
Albertella, L., Le Pelley, M.E., and Copeland, J. (2017). Cannabis use in early adolescence is associated with higher negative schizotypy in females. Eur. Psychiatry J. Assoc. Eur. Psychiatr. 45, 235–241.
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.
Arranz, S., Monferrer, N., Algora, M.J., Cabezas, A., Sole, M., Vilella, E., Labad, J., and Sanchez-Gistau, V. (2018). The relationship between the level of exposure to stress factors and cannabis in recent onset Psychosis. Schizophr. Res. 0.
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.
Bogaty, S.E.R., Lee, R.S.C., Hickie, I.B., and Hermens, D.F. (2018). Meta-analysis of neurocognition in young Psychosis patients with current cannabis use. J. Psychiatr. Res. 99, 22–32.
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.
Carol, E.E., Spencer, R.L., and Mittal, V.A. (2017). The relationship between cannabis use and cortisol levels in youth at ultra high-risk for Psychosis. Psychoneuroendocrinology 83, 58–64.
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.
Degenhardt, L., Saha, S., Lim, C.C.W., Aguilar-Gaxiola, S., Al-Hamzawi, A., Alonso, J., Andrade, L.H., Bromet, E.J., Bruffaerts, R., Caldas-de-Almeida, J.M., et al. (2018). The associations between psychotic experiences and substance use and substance use disorders: findings from the World Health Organization World Mental Health surveys. Addict. Abingdon Engl. 113, 924–934.
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.
Grimm, O., Löffler, M., Kamping, S., Hartmann, A., Rohleder, C., Leweke, M., and Flor, H. (2018). Probing the Endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity. Eur. Neuropsychopharmacol. 0.
Hartberg, C.B., Lange, E.H., Lagerberg, T.V., Haukvik, U.K., Andreassen, O.A., Melle, I., and Agartz, I. (2018). Cortical thickness, cortical surface area and subcortical volumes in Schizophrenia and bipolar disorder patients with cannabis use. Eur. Neuropsychopharmacol. 28, 37–47.
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.
Ibarra-Lecue, I., Mollinedo-Gajate, I., Meana, J.J., Callado, L.F., Diez-Alarcia, R., and Urigüen, L. (2018). Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway. Neuropsychopharmacology 1.
Iseger, T.A., and Bossong, M.G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr. Res. 162, 153–161.
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.
Lodhi, R.J., Wang, Y., Rossolatos, D., MacIntyre, G., Bowker, A., Crocker, C., Ren, H., Dimitrijevic, A., Bugbee, D.A., Loverock, A., et al. (2017). Investigation of the COMT Val158Met variant association with age of onset of Psychosis, adjusting for cannabis use. Brain Behav. 7.
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.
Morales-Muñoz, I., Martínez-Gras, I., Ponce, G., de la Cruz, J., Lora, D., Rodríguez-Jiménez, R., Jurado-Barba, R., Navarrete, F., García-Gutiérrez, M.S., Manzanares, J., et al. (2017). Psychological symptomatology and impaired prepulse inhibition of the startle reflex are associated with cannabis-induced Psychosis. J. Psychopharmacol. Oxf. Engl. 31, 1035–1045.
Mustonen, A., Niemelä, S., Nordström, T., Murray, G.K., Mäki, P., Jääskeläinen, E., and Miettunen, J. (2018). Adolescent cannabis use, baseline prodromal symptoms and the risk of Psychosis. Br. J. Psychiatry 212, 227–233.
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.
Pasman, J.A., Verweij, K.J.H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J.L., Abdellaoui, A., Nivard, M.G., Baselmans, B.M.L., Ong, J.-S., et al. (2018). GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of Schizophrenia. Nat. Neurosci. 21, 1161–1170.
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.
Rentzsch, J., Kronenberg, G., Stadtmann, A., Neuhaus, A., Montag, C., Hellweg, R., and Jockers-Scherübl, M.C. (2017). Opposing Effects of Cannabis Use on Late Auditory Repetition Suppression in Schizophrenia Patients and Healthy Control Subjects. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2, 263–271.
Rigucci, S., Xin, L., Klauser, P., Baumann, P.S., Alameda, L., Cleusix, M., Jenni, R., Ferrari, C., Pompili, M., Gruetter, R., et al. (2018). Cannabis use in early Psychosis is associated with reduced glutamate levels in the prefrontal cortex. Psychopharmacology (Berl.) 235, 13–22.
Roser, P., Pichler, E.-M., Habermeyer, B., Kawohl, W., and Juckel, G. (2018). Impact of Chronic Cannabis Use on Auditory Mismatch Negativity Generation in Schizophrenia Patients. Pharmacopsychiatry.
Rylander, M., Winston, H.R., Medlin, H., Hull, M., and Nussbaum, A. (2018). The association of cannabis use on inpatient psychiatric hospital outcomes. Am. J. Drug Alcohol Abuse 44, 73–84.
Schnakenberg Martin, A.M., Bonfils, K.A., Davis, B.J., Smith, E.A., Schuder, K., and Lysaker, P.H. (2016). Compared to high and low cannabis use, moderate use is associated with fewer cognitive deficits in Psychosis. Schizophr. Res. Cogn. 6, 15–21.
Setién-Suero, E., Neergaard, K., Ramírez-Bonilla, M., Correa-Ghisays, P., Fañanás, L., Crespo-Facorro, B., and Ayesa-Arriola, R. (2017). Cannabis use in male and female first episode of non-affective Psychosis patients: Long-term clinical, neuropsychological and functional differences. PloS One 12, e0183613.
Shah, D., Chand, P., Bandawar, M., Benegal, V., and Murthy, P. (2017). Cannabis induced Psychosis and subsequent psychiatric disorders. Asian J. Psychiatry 30, 180–184.
Shahzade, C., Chun, J., DeLisi, L.E., and Manschreck, T.C. (2018). Patterns in adolescent cannabis use predict the onset and symptom structure of Schizophrenia-spectrum disorder. Schizophr. Res.
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.
Vadhan, N.P., Corcoran, C.M., Bedi, G., Keilp, J.G., and Haney, M. (2017). Acute effects of smoked marijuana in marijuana smokers at clinical high-risk for Psychosis: A preliminary study. Psychiatry Res. 257, 372–374.
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.