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Marijuana: One Cause of Schizophrenia

While it is very likely that other illicit drugs may cause some cases of schizophrenia, marijuana is by far the leading offender, perhaps in part due to it being the most popular and most heavily abused illicit drug.  Marijuana causes temporary paranoid feelings in many users and mild perceptual hallucinations are common.  However, the research evidence is extremely strong, proving beyond any reasonable doubt that marijuana causes a large number of cases of schizophrenia in the modern world.  A number of studies have found marijuana has a stronger link to causing schizophrenia than other drugs.  While some other causes of schizophrenia have decreased, e.g. brain injury and in utero infections, marijuana has made up the difference.

MRI Prove THC Interferes with Inferior Frontal Cortex, Causing Psychotic Symptoms: British doctors took brain scans of 15 healthy volunteers given small doses of two of the active ingredients of cannabis, as well as a placebo. One compound, cannabidiol, or CBD, made people more relaxed. But even small doses of another component, tetrahydrocannabinol, or THC, produced temporary psychotic symptoms in people, including hallucinations and paranoid delusions. In analyzing MRI scans, researchers found that THC interfered with activity in the inferior frontal cortex, a region of the brain associated with paranoia. "THC is switching off that regulator," McGuire said, effectively unleashing the paranoia usually kept under control by the frontal cortex. Philip McGuire, et al. King's College, Institute of Psychiatry. London. International Cannabis and Mental Health Conference. London. May 1, 2007.

Temporary Psychotic Symptoms in 50% of Users; Very Harmful to Schizophrenics: In a study of THC on 150 healthy volunteers and 13 people with stable schizophrenia, nearly half of the healthy subjects experienced psychotic symptoms when given the drug. While the doctors expected to see marijuana improve the conditions of their schizophrenic subjects since their patients reported that the drug calmed them they found that the reverse was true. "We found that cannabis is very bad for people with schizophrenia," D'Souza said. The study was stopped prematurely because the impact was so pronounced that it would have been unethical to test it on more people with schizophrenia. Deepak Cyril D'Souza, et al. Yale University. International Cannabis and Mental Health Conference. London. May 1, 2007.

Marijuana and Tobacco Linked to Psychosis in Predeposed: Cannabis abuse was assessed in 48 individuals identified as at risk for psychosis based on subsyndromal psychotic symptoms and/or family history from the Cognitive Assessment and Risk Evaluation (CARE) Program, a longitudinal program for individuals who are "at risk" for developing a psychotic disorder. At 1 year follow-up, 6 of the 48 (12.5%) at risk subjects had made the transition to psychosis. Of the 32 subjects who had no use or minimal cannabis use, one subject (3.1%) converted to psychosis. Of the 16 subjects who met criteria for cannabis abuse/dependence, five (31.3%) converted to psychosis. Nicotine use was also found to be significantly associated with later conversion. Cannabis abuse and risk for psychosis in a prodromal sample. Kristensen K, et al. University of California San Diego. Psychiatry Res 2007 May 30;151(1-2):151-4.

OBJECTIVE: The purpose was to determine the prevalence of substance use and its impact on outcome 3 years after presentation for a first-episode of psychosis. METHOD: Subjects were 203 consecutive admissions to an early psychosis program. Assessments included substance use, positive, negative and depressive symptoms and social functioning. Assessments occurred at baseline, and 1-, 2- and 3-year follow-ups. RESULTS: The prevalence of substance misuse was high with 51% having a substance use disorder (SUD), 33% with cannabis SUD and 35% with an alcohol SUD. Numbers with an alcohol SUD declined considerably by 1 year and for cannabis SUD by 2 years. Substance misuse was significantly associated with male gender, young age and age of onset and cannabis misuse with increased positive symptoms. CONCLUSION: This study confirms the high rates of substance misuse, in particular cannabis, in first-episode psychosis. It further demonstrates that these rates can be reduced. Patterns, predictors and impact of substance use in early psychosis: a longitudinal study. Addinton J, et al. University of Toronto. .  Acta Psych Scand 2007 Apr;115(4):304-9.

BACKGROUND: Cannabis use appears to exacerbate psychotic symptoms and increase risk of psychotic relapse. However, the relative contribution of cannabis use compared with other risk factors is unclear. The influence of psychotic symptoms on cannabis use has received little attention. AIMS: To examine the influence of cannabis use on psychotic symptom relapse and the influence of psychotic symptom severity on relapse in cannabis use in the 6 months following hospital admission. METHOD: At baseline, 84 participants with recent-onset psychosis were assessed and 81 were followed up weekly for 6 months, using telephone and face-to-face interviews. RESULTS: A higher frequency of cannabis use was predictive of psychotic relapse, after controlling for medication adherence, other substance use and duration of untreated psychosis. An increase in psychotic symptoms was predictive of relapse to cannabis use, and medication adherence reduced cannabis relapse risk. CONCLUSIONS: The relationship between cannabis use and psychosis may be bidirectional, highlighting the need for early intervention programmes to target cannabis use and psychotic symptom severity in this population. Psychotic symptom and cannabis relapse in recent-onset psychosis. Prospective study. Hides L, et al. Griffith University, Melbourne, Victoria, Australia. . Br J Psychiatry 2006 Aug;189:137-43.

BACKGROUND: Cannabis use is common in patients with bipolar disorder, however little is known about cannabis as a risk factor for mania. In order to investigate the association between exposure to cannabis and subsequent development of manic symptoms whilst controlling for psychotic symptoms, a longitudinal population-based study was carried out. METHODS: 4815 individuals aged 18 to 64 years were interviewed using the Composite International Diagnostic Interview at baseline, 1 year follow up and 3 year follow up, including assessment of substance use, manic symptoms and psychotic symptoms. RESULTS: Use of cannabis at baseline increased the risk for manic symptoms during follow-up (adjusted OR 2.70, 95% CI: 1.54, 4.75), adjusted for age, sex, educational level, ethnicity, single marital status, neuroticism, use of other drugs, use of alcohol, depressive symptoms and manic symptoms at baseline. The association between cannabis use and mania was independent of the prevalence and the incidence of psychotic symptoms. There was no evidence for reverse causality, as manic symptoms at baseline did not predict the onset of cannabis use during follow-up (OR = 0.35, 95% CI: 0.03, 3.49). LIMITATIONS: As 3 years is a relative short period of follow-up, long-term effects of cannabis use on mania outcomes could not be detected. CONCLUSION: The results suggest that cannabis use may affect population expression of manic symptoms (and subsequent risk to develop bipolar disorder [Regeer, E.J., Krabbendam, L., R, DE Graaf, Ten Have, M., Nolen, W.A., Van Os, J., 2006. A prospective study of the transition rates of subthreshold (hypo)mania and depression in the general population. Psychol Med, 1-9.]). These findings may not be due to the emergence of psychotic symptoms or the effects of self-medication. Cannabis use and expression of mania in the general population. Henquet C, et al. Maastricht University, The Netherlands. J Affective Disorder 2006 Oct;95(1-3):103-10.

ABSTRACT : Several studies suggest a high comorbidity of substance abuse and schizophrenia, associated with higher frequency of relapse, more positive symptoms and depression, cognitive impairment, poorer outcome and treatment response. A high incidence of substance abuse is also observed in first-episode patients. Among patients with substance abuse, the onset precedes the onset of psychosis of several years in most cases.All the patients with a first episode of schizophrenia, at first admission to the Psychiatric Service of Diagnosis and Treatment of Ospedale Maggiore of Milan during the years 1990 to 2004, have been included in our study.The clinical evaluation has been obtained considering the following items of Brief Psychiatric Rating Scale (BPRS): conceptual disorganization, depressed mood, hostility, hallucinations, unusual content of thought.The results showed that 34.7% of first-episode schizophrenic patients had a lifetime history of substance abuse. The age of onset of schizophrenia is significantly lower for drug abusers than for patients without any type of abuse and for alcohol abusers (p < 0.005). In multi drug abusers, cannabis resulted the most frequently used (49%), followed by alcohol (13%), and cocaine (4%). Substance abusers have obtained a significant higher score in "thought disturbance" item (p < 0.005) and in "hostility" item (p < 0.005) compared to non substance abusers. Non drug abusers showed lower mean scores of "hostility" item compared to cocaine abusers and multi drug abusers (p < 0.005).Our findings seem to indicate that substance abuse in the early course of illness determines an earlier onset of schizophrenia and increases severity of some psychotic symptoms like "hallucination" and "unusual content of thought". Therefore persons incurring a risk of schizophrenia may be warned of the possible relation between substances and psychosis and have to be counselled against the use of them. Substance abuse in first-episode schizophrenic patients: a retrospective study. Mauri M, et al. University of Milan, Italy. . Clin Pract Epidem Mental Health 2006 Mar 23;2:4.

BACKGROUND: Substance use may be a risk factor for the onset of schizophrenia. AIMS: To examine the association between substance use and age at onset in substance use and age at onset in a UK, inner-city sample of people with recent-onset schizophrenia. METHOD: The study sample consisted of 152 people recruited to the West London First-Episode Schizophrenia Study. Self-reported data on drug and alcohol use, as well as information on age at onset of psychosis, were collected.Mental state, cognition (IQ, memory and executive function) and social function were also assessed. RESULTS: In total, 60% of the participants were smokers, 27% reported a history of problems with alcohol use, 35% reported current substance use (not including alcohol), and 68% reported lifetime substance use (cannabis and psychostimulants were most commonly used).Cannabis use and gender had independent effects on age at onset of psychosis, after adjusting for alcohol misuse and use of other drugs. CONCLUSIONS: The strong association between self-reported cannabis use and earlier onset of psychosis provides further evidence that schizophrenia may be precipitated by cannabis use and/or that the early onset of symptoms is a risk factor for cannabis use.  Comorbid substance use and age at onset of schizophrenia. Barnes TR, et al. Imperial College Faculty of Medicine, London, UK. . Br J Psychiatry 2006 Mar;188:237-42.

BACKGROUND: Few studies have examined samples of people with cannabis-induced psychotic symptoms. AIMS: To establish whether cannabis-induced psychotic disorders are followed by development of persistent psychotic conditions, and the timing of their onset. METHOD: Data on patients treated for cannabis-induced psychotic symptoms between 1994 and 1999 were extracted from the Danish Psychiatric Central Register. Those previously treated for any psychotic symptoms were excluded. The remaining 535 patients were followed for at least 3 years. In a separate analysis, the sample was compared with people referred for schizophrenia-spectrum disorders for the first time, but who had no history of cannabis-induced psychosis. RESULTS: Schizophrenia-spectrum disorders were diagnosed in 44.5% of the sample. New psychotic episodes of any type were diagnosed in 77.2%. Male gender and young age were associated with increased risk. Development of schizophrenia-spectrum disorders was often delayed, and 47.1% of patients received a diagnosis more than a year after seeking treatment for a cannabis-induced psychosis. The patients developed schizophrenia at an earlier age than people in the comparison group (males, 24.6 v. 30.7 years, females, 28.9 v. 33.1 years). CONCLUSIONS: Cannabis-induced psychotic disorders are of great clinical and prognostic importance. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Arendt M, et al. Aarhus University Hospital, Denmark. . Br J Psychiatry 2005 Dec;187:510-5.

AIMS: To investigate if associations between cannabis use and psychotic symptoms occur independently, or occur as a consequence of previous-other types of-psychopathology. METHODS: A 14-year follow-up study of 1580 initially 4- to 16-year-olds who were drawn randomly from the Dutch general population was conducted. At initial assessment, psychopathology was assessed with the Child Behavior Checklist. Across the 14-year follow-up period, cannabis use and psychotic symptoms were assessed with the Composite International Diagnostic Interview (CIDI). Because cannabis use is generally condoned in The Netherlands, false-negative reports of cannabis use may occur less frequently than in countries with stricter drug policies, which supports the value of the present study. RESULTS: Survival analyses indicated that the association between cannabis use and psychotic symptoms occurred independently of initial CBCL scores. CONCLUSIONS: The link between cannabis use and psychotic symptoms is specific, and does not depend on the earlier presence of other types of psychopathology. This indicates that research aimed at unraveling mechanisms that are responsible for this specific association is useful. Further, given the fact that cannabis use seemed to be a specific risk factor for future psychotic symptoms, prevention aimed against cannabis use may prohibit the onset of psychotic symptoms in vulnerable individuals. Cannabis--psychosis pathway independent of other types of psychopathology. Ferdinand RF, et al. Erasmus Medical Center. Rotterdam, The Netherlands. . Schizophrenia Res 2005 Nov 15;79(2-3):289-95.

Cannabis-Induced Psychosis Often Leads to Schizophrenia: In a Danish study 535 patients with cannabis-induced psychosis with no previous history of psychosis were followed for at least 3 years. These were compared to people referred for schizophrenia-spectrum disorders for the first time, but who had no history of cannabis-induced psychosis. Schizophrenia-spectrum disorders were diagnosed in 44% of the cannabis-induced psychosis during follow-up. New psychotic episodes of any type were diagnosed in 77%. Male gender and young age were associated with increased risk. Development of schizophrenia-spectrum disorders was often delayed, and 47% of patients received a diagnosis more than a year after seeking treatment for a cannabis-induced psychosis. The patients developed schizophrenia at an earlier age than people in the comparison group (males, 24.6 v. 30.7 years, females, 28.9 v. 33.1 years). Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Arendet M, et al. Aarhus University Hospital, Denmark. . Br J Psychiatry 2005 Dec;187:510-5.

Schizophrenics Using Marijuana Did More Poorly: In a case control study, 50 schizophrenic patients with co-morbid misuse of cannabis were compared to 50 without. Schizophrenic patients with cannabis use were younger and had younger age at onset of illness. They had more relapses and more contacts with psychiatric services including the police. Patients with comorbid cannabis use had poor drug compliance and their relapses were preceded by poor drug compliance.

Marijuana May Shrink Brain Area Leading to Schizophrenia: In a study of prefrontal grey and white matter regions in patients experiencing a first episode of schizophrenia with an additional diagnosis of cannabis use or dependence (n=20) compared with similar patients with no cannabis use (n=31) and healthy volunteers (n=56), patients who used cannabis had less anterior cingulate grey matter compared with both patients who did not use cannabis and healthy volunteers. Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. Szeszko PR, et al. Zucker HillsideHospital, Glen Oaks, NY. [email protected].. Br J Psychiatry 2007 Mar;190:230-6.

Cannabis Causes Schizophrenia: In 152 people recruited to the West London First-Episode Schizophrenia Study, 60% were smokers, 27% problems with alcohol use, and 68% reported lifetime substance use (cannabis and psychostimulants).Cannabis use and gender had independent effects on age at onset of psychosis, after adjusting for alcohol misuse and use of other drugs. The strong association between self-reported cannabis use and earlier onset of psychosis provides further evidence that schizophrenia may be precipitated by cannabis use and/or that the early onset of symptoms is a risk factor for cannabis use.

Schizophrenia Increased in US Army After Marijuana: Schizophrenia in US Army in Europe jumped from 1/1000 to 38/1000 over the 5-year period from 1967-1971. Tennant and Groesbeck interpreted change as due to rapid growth cannabis use. Arch Gen Psyc 27:133-6, 72

Dutch Prospective Study Finds Causal Link with Major Increase in Schizophrenia from Marijuana: A three year follow up of a Dutch cohort of 4045 people free of psychosis and 59 with a baseline diagnosis of psychotic disorder showed a strong association between use of cannabis and psychosis. Am J Epidemiol 2002; 156:319-327; Cannabis Use and Psychosis: A Longitudinal Population-based Study. J. van Os, M. Bak, M. Hanssen, R. V. Bijl, R. de Graaf and H. Verdoux; Baseline cannabis use predicted the presence at follow-up of any level of psychotic symptoms (OR = 2.76), as well as a severe level of psychotic symptoms (OR = 24.17), and clinician assessment of the need for care for psychotic symptoms (OR = 12.01). The effect of baseline cannabis use was stronger than the effect at 1-year and 3-year follow-up, and more than 50% of the psychosis diagnoses could be attributed to cannabis use. On the additive scale, the effect of cannabis use was much stronger in those with a baseline diagnosis of psychotic disorder (risk difference, 54.7%) than in those without (risk difference, 2.2%; p for interaction = 0.001). Results confirm previous suggestions that cannabis use increases the risk of both the incidence of psychosis in psychosis-free persons and a poor prognosis for those with an established vulnerability to psychotic disorder.

Schizophrenia Linked to Marijuana in Swedish Military: Schizophrenia is 2.4 times more likely in draftees with any marijuana use and 6 times more likely if used 50 times or more by age 20. There was no family history to explain the increased cases and they were typically of onset rapid often with paranoid features. Andreasson, Lancet 88;i:592-3.

27 Year f/u of Swedish Military Study: BMJ 2002;325:1199 ( 23 November ); Virtually identical conclusions with further refinement of data. Finds marijuana the cause of 30% of schizophrenia developing in recruits which included 98% of Swede males. Stanley Zammit at the University of Cardiff, UK, evaluated data on over 50,000 men who had been Swedish military conscripts in 1969 and 1970. The new analysis revealed a dose-dependant relationship between the frequency of cannabis use and schizophrenia. This held true in men with no psychotic symptoms before they started using cannabis, suggesting they were not self-medicating.

Prospective New Zealand Study Finds Marijuana Triples Schizophreniform Disorder: A birth cohort of 1037 individuals born in Dunedin, New Zealand, in 1972-3. Started measuring for psychosis age 11, drug use ages 15 and 18. 26 year f/u. First prospective study proving causation. divided the sample into three groups based on cannabis use at ages 15 and 18. The 494 controls (65.1% of the sample) had reported using cannabis "never" or "once or twice" at both ages; cannabis users by age 18 (236; 31.1%) first reported using cannabis "three times or more" at age 18; and cannabis users by age 15 (29; 3.8%) had reported using cannabis "three times or more" at age 15 (all of whom continued to use cannabis at age 18). Cannabis use is associated with an increased risk of experiencing schizophrenia symptoms, even after psychotic symptoms preceding the onset of cannabis use are controlled for, indicating that cannabis use is not secondary to a pre-existing psychosis. Secondly, early cannabis use (by age 15) confers greater risk for schizophrenia outcomes than later cannabis use (by age 18). The youngest cannabis users may be most at risk because their cannabis use becomes longstanding. Risk was specific to cannabis use, as opposed to use of other drugs, and early cannabis use did not predict later depression. A tenth of the cannabis users by age 15 in our sample (3/29) developed schizophreniform disorder by age 26 compared with 3% of the remaining cohort (22/730). Our findings suggest that cannabis use among psychologically vulnerable adolescents should be strongly discouraged by parents, teachers, and health practitioners. Policy makers and law makers should concentrate on delaying onset of cannabis use. BMJ 2002;325:1212-1213 ( 23 November ); Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study; Louise Arseneault, Mary Cannon, Richie Poulton, Robin Murray, Avshalom Caspi, Terrie E Moffitt. While age 15 marijuana use was not related to later depression, young people who had used cannabis three times or more by age 18 were more likely to have a depressive disorder at age 26, even after use of other drugs was controlled for.

Schizophrenic Use Marijuana More Often Than Other Patients with Other Diagnosis: Lifetime prevalence cannabis higher in schizophrenia than with other psych diagnoses. Weller, Lancet, 88;i:997.

Genetics Important in Abuse & Dependence: Ken Kendler of U Virginia in 335 female twin pairs says genetics moderate impact on probability of ever using and strong impact on risk of heavy use, abuse, and dependence with family and social environment playing big role in ever using but little role in developing heavy use or abuse. Am J Psychiatry 98;155:1016-22

Marijuana Receptors: Cannabinoid receptor CB1 in brain neurons coupled via G proteins modulating adenylate cyclase and ion channels. CB@ in immune system inhibits adenylate cyclase. SR141716A a selective antagonist reduces alcohol intake in rats. Cannabinoids may also work through 5-HT receptors and regulate mesolimbic dopamine transmission. Which is a final common pathway for many drugs of abuse. Tolerance to cannabinoids is well established. The antagonist precipitate clear withdrawal symptoms. In mice which have been chronically exposed to THC. This reinforces already existing evidence that marijuana is addictive. With physical dependence. CB2 cannabinoid effects inhibit T-cell-dependent humoral immune responses. Anandamide a ethanolamide fatty acid which may be neurotransmitters. It activates CB1 similar to synthetic agonist CP55-940.n Stephen Stahl UCSD J Clin Psychiatry 11/98 59:566-7

Marijuana Linked to Schizotypal Personality: Higher scores on the Schizotypal Personality Questionnaire and the Magical Ideation Scale characterized the regular and past or occasional users compared with those who had never used cannabis. The co-occurrence of cannabis use and schizotypal traits appeared to be independent of anxiety and depression. 232 healthy 18-25yo studied. Lyon France. Psychiatry Res 2002 Jan 31;109(1):27-35

Illicit Drugs in 38%: Duke study of schizophrenic admissions found 16% admitted using marijuana, methamphetamine, opiates, cocaine, PCP within past 3 moths, 12% had positive urines and 31% positive hair samples which 10% refused to allow to be gathered. Detection of illicit substance use among persons with schizophrenia by radioimmunoassay of hair. Swartz MS, Swanson JW, Hannon MJ. Psychiatr Serv. 2003 Jun;54(6):891-5

Illicit Drugs: Dutch Psychotics Use Marijuana 3 Times More Often: 33% Netherland psychotics used cannabis in month before admission and 32% used monthly all year with 26% having daily usage for at least two weeks. Only 10% general 16-24 yos used in previous month. Acta Psy Scan 02;105:440-3

Illicit Drug Use Doubles Schizophrenia in Israeli Male Teens with Behavioral Problems: Military screens all 16-17yos. Of 270,000, 50,000 interviewed due to behavioral concerns. In f/u, hospitalization for schizophrenia double for those using drugs. Self-reported drug abuse in male adolescents with behavioral disturbances, and follow-up for future schizophrenia. Weiser M, Reichenberg A, Rabinowitz J, Kaplan Z, Caspi A, Yasvizky R, Mark M, Knobler HY, Nahon D, Davidson M. Biol Psychiatry. 2003 Sep 15;54(6):655-60