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Fernandez-Espejo and colleagues suggested that the endocannabinoid system is altered in schizophrenia and that dysregulation of this system, perhaps induced by exogenous cannabis, can interact with neurotransmitter systems in a way so that a "cannabinoid hypothesis" can be integrated with other neurobiologic hypotheses (eg, those involving dopamine and glutamate).

Evidence Accumulates for Links Between Marijuana and Psychosis

Michael T. Compton, MD, MPH


A number of studies in recent years have revealed complex links between marijuana use and psychotic symptoms and diagnosable psychotic disorders like schizophrenia. Although a thorough review of this broad literature is beyond the purview of this brief communication, two avenues of research will be succinctly summarized, pertaining to (1) associations between cannabis use and clinical manifestations of psychosis, and (2) the biologic plausibility of the observed links.

Cannabis and Psychosis

Diverse studies suggest that cannabis use is associated with psychotic phenomenology. First, in addition to being the most abused illicit substance in the general US population, cannabis is clearly the most abused illegal drug among individuals with schizophrenia.[1,2] Furthermore, the initiation of cannabis use among those with psychotic disorders often precedes the onset of psychosis by several years.[1,3,4]

Second, cannabis use in adolescence is increasingly recognized as an independent risk factor for psychosis and schizophrenia.[5-7] That is, several epidemiologic studies suggest that cannabis use is a component cause of schizophrenia.[8,9]

Very recently, McGrath and colleagues[10] reported that early cannabis use is associated with psychosis-related outcomes (having a nonaffective psychotic disorder, scoring in the highest quartile of the Peters Delusions Inventory,[11] and reporting hallucinations) in a cohort of 3801 individuals assessed at age 18-23 years. Findings among 228 sibling pairs in that study reduce the likelihood that unmeasured confounding variables account for the results.[10]

Third, cannabis use may interact with genetic factors to elevate risk for psychotic disorders. One sentinel study demonstrated that the catechol-O-methyltransferase Val158Met functional polymorphism moderates the effects of adolescent-onset cannabis use on the later development of psychosis.[12]

Fourth, preliminary research suggests that cannabis use before the manifestation of psychiatric symptoms may be associated with an earlier age at onset of psychotic symptoms,[13] and perhaps even an earlier onset of prodromal symptoms.[14] We found that simply classifying first-episode psychosis patients according to their maximum frequency of use before onset of psychotic symptoms (ie, categorizing into none, ever, weekly, or daily use) revealed no significant effects of cannabis use on risk for onset, but analyzing the change in frequency of use before onset (using time-dependent covariates), revealed that progression to daily cannabis use was associated with age at onset.[14]

Fifth, aside from studies linking cannabis use and psychotic disorders, an increasing body of research suggests a potential association between cannabis use and schizotypal symptoms, or psychosis-proneness, in the general population.[15,16]

Several lines of evidence support the potential biologic plausibility of these links between cannabis use and psychosis.

First, exogenous (eg, Δ-9-tetrahydrocannabinol) and endogenous cannabinoids (eg, anandamide) exert their effects (such as modulating the release of neurotransmitters including dopamine and glutamate) by interactions with specific cannabinoid (CB1) receptors that are distributed in brain regions implicated in schizophrenia.

Second, several studies have shown an increased CB1 receptor density in brain regions of interest in schizophrenia, including the dorsolateral prefrontal cortex and the anterior cingulate cortex.[17,18]

Third, other studies report elevated levels of endogenous cannabinoids in the blood and cerebrospinal fluid of patients with schizophrenia.[19-21]

Fourth, acute, controlled administration of Δ-9-tetrahydrocannabinol causes both patients and controls to experience transient increases in cognitive impairments and schizophrenia-like positive and negative symptoms.[22]

In summarizing these and many other findings, Fernandez-Espejo and colleagues[23] have suggested that the endocannabinoid system is altered in schizophrenia and that dysregulation of this system, perhaps induced by exogenous cannabis, can interact with neurotransmitter systems in a way so that a "cannabinoid hypothesis" can be integrated with other neurobiologic hypotheses (eg, those involving dopamine and glutamate).


In sum, a growing body of clinical and epidemiologic research suggests significant but complex links between cannabis use and psychosis. Concurrently, ongoing neurobiologic research is revealing findings in the endocannabinoid system that appear to support the biologic plausibility of such links. It should be noted that much of the research conducted to date does not allow for causal determinations. Ongoing research of varying designs will undoubtedly enlighten the field.


1. Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent onset schizophrenic disorders. Arch Gen Psychiatry. 1994;51:273-279. Abstract
2. Bersani G, Orlandi V, Kotzalidis GD, Pancheri P. Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes. Eur Arch Psychiatry Clin Neurosci. 2002;252:86-92. Abstract
3. Allebeck P, Adamsson C, Engstrom A, Rydberg U. Cannabis and schizophrenia: a longitudinal study of cases treated in Stockholm county. Acta Psychiatr Scand. 1993;88:21-24. Abstract
4. Stewart T, Goulding SM, Pringle M, Esterberg ML, Compton MT. A descriptive study of nicotine, alcohol, and cannabis use in urban, socially-disadvantaged, predominantly African-American patients with first-episode nonaffective psychosis. Clin Schizophr Relat Psychoses. 2010;3:217-225.
5. Smit F, Boiler L, Cuijpers P. Cannabis use and the risk of later schizophrenia: a review. Addiction. 2004;99:425-430. Abstract
6. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19:187-194. Abstract
7. Weiser M, Noy S. Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci. 2005;7:81-85. Abstract
8. Andréasson S, Allebeck P, Rydberg U. Schizophrenia in users and nonusers of cannabis: a longitudinal study in Stockholm County. Acta Psychiatr Scand. 1989;79:505-510. Abstract
9. Zammit S, Allebeck P, Andréasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325:1199-1203. Abstract
10. McGrath J, Welham J, Scott J, et al. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. 2010 Mar 1. [Epub ahead of print]
11. Peters ER, Joseph SA, Garety PA. Measurement of delusional ideation in the normal population: introducing the PDI (Peters et al. Delusions Inventory). Schizophr Bull. 1999;25:553-576. Abstract
12. Caspi A, Moffitt TE, Cannon M, et al. 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. 2005;57:1117-1127. Abstract
13. Compton MT, Ramsay CE. The impact of pre-onset cannabis use on age at onset of prodromal and psychotic symptoms. Primary Psychiatry. 2009;16:35-43.
14. Compton MT, Kelley ME, Ramsay CE, et al. Association of pre-onset cannabis, alcohol, and tobacco use with the age at onset of prodrome and age at onset of psychosis in first-episode patients. Am J Psychiatry. 2009;166:1251-1257. Abstract
15. Williams JH, Wellman NA, Rawlins JNP. Cannabis use correlates with schizotypy in healthy people. Addiction. 1996;91:869-877. Abstract
16. Compton MT, Goulding SM, Walker EF. Cannabis use, first-episode psychosis, and schizotypy: a summary and synthesis of recent literature. Curr Psychiatry Rev. 2007;3:161-171.
17. Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. 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. 2001;103:9-15. Abstract
18. Zavitsanou K, Garrick T, Huang XF. Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Progr Neuropsychopharmacol Biol Psychiatry. 2004;28:355-360.
19. Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoids in schizophrenia. Neuroreport. 1999;10:1665-1669. Abstract
20. De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signaling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2:5-14. Abstract
21. Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004;29:2108-2114. Abstract
22. D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005;57:594-608. Abstract
23. Fernandez-Espejo E, Viveros MP, Núñez L, Ellenbroek BA, Rodriguez de Fonseca F. Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology. 2009;206:531-549.





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