Marijuana receptor gene abnormality in schizophrenia

July 01, 2002

The cannabinoid hypothesis for the pathogenesis of schizophrenia is based on the clinical facts that abuse of cannabis (marijuana) could precipitate the psychotic state, with hallucinations and delusions resembling schizophrenia and worsen positive symptoms of schizophrenia, even under regular medication of antipsychotics. Cannabinoid consumption could result in poor outcome and liability to relapse for schizophrenics. In addition, heavy cannabis users may develop an amotivational syndrome, reminiscent of some of the negative symptoms of schizophrenia. A Swedish cohort study showed that cannabis use before 18 years of age raises the incident rate of schizophrenia six-fold. Another study showed that administration of delta-9-hydrocannabinol to normal volunteers induced cognitive impairment of three dimensions resembling closely that of schizophrenic patients. The hallucinogenic action of cannabis and marijuana mediated the central cannabinoid receptor, G-protein-coupled receptor CB1, which was discovered in 1988. CB1 receptors were expressed abundantly throughout the brain, especially in substantia nigra, globus pallidus, hippocampus and cerebellum. CB1 receptors are encoded by the CNR1 gene (MIM114610), which was cloned by Matsuda et al in 1992. CB1 is located at 6q14-q15, which was included in a schizophrenia susceptibility locus, 6q13-q26, revealed by Cao et al using two independent series of pedigrees, which was designated by Schizophrenia 5 (SCZ5, OMIM 603175). Recently, two polymorphisms, AAT repeats microsatellite in the 3' flanking region and 1359 G/A polymorphism at codon 453 in the coding exon of the CNR1 gene, were reported.

To examine the cannabinoid hypothesis for schizophrenia, the authors examined these two polymorphisms in the cannabinoid receptor 1 (CNR1) gene in the Japanese population. Specifically, they examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotype distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3' flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% Cl (191-2.69), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% Cl (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type.

The hebephrenic type schizophrenia, which has been shown to be associated with the CNR1 gene in the present study, is characterized by predominant negative symptoms such as blunted affect, disorganized thought and deterioration of personality. Such symptomatic features of hebephrenic schizophrenia bear resemblance to chronic cannabinoid psychoses. Although acute use of cannabis can induce diverse types of psychotic state, such as panic reaction, confusional state, paranoid state and mania, chronic cannabis users often develop an 'amotivational syndrome typified by a diminution of ambition, productivity and motivation, which are often observed in hebephrenic schizophrenics. In addition, cannabinoid use affects cognitive function such as information processing and planning tasks. Such cognitive dysfunction is prominent in chronic schizophrenics like hebephrenics. Therefore, the endogenous cannabinoid system may be activated in the brain of patients with schizophrenia, especially with the hebephrenic type.
ARTICLE: "CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia"

AUTHORS: H Ujike, M Takaki, K Nakata, Y Tanaka, T Takeda, M Kodama, Y Fujiwara, A Sakai and S Kuroda

Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; Zikei Hospital, Okayama, Japan; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, USA; Takami Hospital, Okayama, Japan; Takaoka Hospital, Himeji, Japan; Kasaoka Hospital, Kasaoka, Japan

Citation source: Molecular Psychiatry 2002 Volume 7, number 5, pages 515-518. doi:10.1038/

For further information on this work, please contact H Ujike, MD, PhD, Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: +81-86-235-7242; FAX: +81-86-235-7246; E-mail:

Molecular Psychiatry is published by the Nature Publishing Group.

Editor: Julio Licinio, M.D.; phone: +1-310-825-7113; FAX: +1-310-206-6715; e-mail:

For a copy of this article, please contact Frank Sissingh, editorial assistant, e-mail:


Molecular Psychiatry

Related Schizophrenia Articles from Brightsurf:

Schizophrenia: When the thalamus misleads the ear
Scientists at the University of Geneva (UNIGE) and the Synapsy National Centre of Competence in Research (NCCR) have succeeded in linking the onset of auditory hallucinations - one of the most common symptoms of schizophrenia - with the abnormal development of certain substructures of a region deep in the brain called the thalamus.

Unlocking schizophrenia
New research, led by Prof. LIU Bing and Prof. JIANG Tianzi from the Institute of Automation of the Chinese Academy of Sciences and their collaborators have recently developed a novel imaging marker that may help in the personalized medicine of psychiatric disorders.

Researchers discover second type of schizophrenia
In a study of more than 300 patients from three continents, over one third had brains that looked similar to healthy people.

New clues into the genetic origins of schizophrenia
The first genetic analysis of schizophrenia in an ancestral African population, the South African Xhosa, appears in the Jan.

Dietary supplement may help with schizophrenia
A dietary supplement, sarcosine, may help with schizophrenia as part of a holistic approach complementing antipsychotic medication, according to a UCL researcher.

Schizophrenia: Adolescence is the game-changer
Schizophrenia may be related to the deletion syndrome. However, not everyone who has the syndrome necessarily develops psychotic symptoms.

Study suggests overdiagnosis of schizophrenia
In a small study of patients referred to the Johns Hopkins Early Psychosis Intervention Clinic (EPIC), Johns Hopkins Medicine researchers report that about half the people referred to the clinic with a schizophrenia diagnosis didn't actually have schizophrenia.

The ways of wisdom in schizophrenia
Researchers at UC San Diego School of Medicine report that persons with schizophrenia scored lower on a wisdom assessment than non-psychiatric comparison participants, but that there was considerable variability in levels of wisdom, and those with higher scores displayed fewer psychotic symptoms.

Recognizing the uniqueness of different individuals with schizophrenia
Individuals diagnosed with schizophrenia differ greatly from one another. Researchers from Radboud university medical center, along with colleagues from England and Norway, have demonstrated that very few identical brain differences are shared amongst different patients.

Resynchronizing neurons to erase schizophrenia
Today, a decisive step in understanding schizophrenia has been taken.

Read More: Schizophrenia News and Schizophrenia Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to