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Does Using Marijuana Increase the Risk for Developing Schizophrenia?

A. Eden Evins, MD, MPH (Chair)

Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston

Alan I. Green, MD

Department of Psychiatry and the Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and the Dartmouth Center for Clinical and Translational Science, Hanover, New Hampshire

John M. Kane, MD

Department of Psychiatry, The Hofstra North Shore-Long Island Jewish School of Medicine, Uniondale; the Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks; and Behavioral Health Services, North Shore-Long Island Jewish Health System, New Hyde Park, New York

Sir Robin M. Murray, MD, FRS

Department of Psychosis, Institute of Psychiatry, King’s College London, London, United Kingdom

Cannabis, or marijuana, is one of the most commonly used illicit drugs, and it has been connected to an increased risk of schizophrenia in vulnerable adolescents. Schizophrenia, a chronic and disabling brain disorder characterized by a breakdown in thought processes and unusual behavior, typically presents in young people between the ages of 18 and 25 years.

Dr Evins assembled an international group of experts to discuss the risk factors for schizophrenia, the potency and effects of cannabis use on adolescents, the effects of concurrent drug use with cannabis on schizophrenia risk, and the effects of legalizing marijuana on adolescents.

What Are the Risk Factors for Schizophrenia?

Dr Kane: Determining the risk for schizophrenia is complicated because it involves potential gene-environment interactions. Someday we may have genetic markers that will help determine a person’s risk for schizophrenia, but right now we can only watch for early symptoms of the disease in young patients, such as deterioration in school performance or odd thoughts or behaviors.

Dr Murray: Schizophrenia results from a number of different risk factors,1 including genetic predisposition, prenatal problems, insult to the brain during development, childhood adversity, and exposure to certain drugs.

For example, evidence2 suggests that people with a family history of psychosis or a “psychosis-prone” or paranoid personality have an increased risk of developing schizophrenia. And, other research3,4 focusing on genetic susceptibility has suggested that variation in the AKT1 and COMT genes may cause some individuals to be more susceptible to the psychotogenic effects of cannabis. However, we are still far from the stage where we can go to a music festival and genotype everybody and advise half of the participants to avoid cannabis and tell the other half to go ahead and smoke as they like.

Dr Evins: Schizophrenia is highly heritable, and about 80% of the liability is attributable to genetic factors.5 Genetic risk may emerge in 2 ways: (1) the interaction of common variants of many genes, each having small effects, and (2) the rare occurrence of genetic variants such as deletions or duplications.6 The consequences of cannabis use can be severe in a person who already has the underlying genetic risk factors.

Dr Kane: People who have serious psychiatric illnesses should also be warned about marijuana use.

Dr Evins: Patients often think that cannabis makes them feel better or more relaxed, but they come back clinically worse. Clinicians should alert patients to this.

How Does Early or Heavy Cannabis Use Affect Adolescents?

Dr Evins: Early, heavy cannabis use seems to be associated with the greatest risk for psychosis.

Dr Green: The data7,8 suggest that cannabis use in early adolescence (ie, early cannabis use) is associated with an earlier onset of schizophrenia in a vulnerable population.

Dr Murray: Young people who become paranoid or temporarily deluded after using marijuana tend to think they had a bad trip and do not use cannabis again. In this way, they lessen their vulnerability of developing psychosis. Other people who enjoy cannabis at first and do not develop psychotic reactions until months or years later may find themselves dependent and have difficulty stopping cannabis use.

Dr Evins: Some people think that, during the prodromal period of schizophrenia when adolescents are less socially adjusted and less likely to be doing well in school, they are simply more likely to be vulnerable to peer pressure to use marijuana. Do we agree that marijuana use in someone who is already developing schizophrenia is more than a coincidence and could be a risk factor?

AV 1. Mean Psychotic Symptoms by Frequency of Cannabis Use at 18, 21, and 25 Years (00:30)

Data from Fergusson et al9

Dr Murray: Yes. A 25-year longitudinal study9 that measured cannabis use and psychotic symptoms at 18, 21, and 25 years of age (N = 1,055) found that daily cannabis users at 18 and 21 had higher rates of psychotic symptoms than the nonusers at 25; however, psychotic symptoms were associated with subsequent lower cannabis consumption (AV 1). The data suggested that the direction of causality is from cannabis use to psychotic symptoms, but this does not mean that cannabis use is a necessary or single cause of schizophrenia.

Dr Green: It does appear that early cannabis use predisposes people to a greater risk for developing psychosis than does later use.10

More

Dr Murray: Chronically smoking marijuana in early adolescence is associated with a greater risk for psychosis. In another report of the Dunedin study,10 more than 90% of the 15-year-olds who used cannabis had not stopped by age 18. Other research11 suggests that white matter connectivity could be more affected depending on the age at which regular cannabis use begins.

How Does the Potency of Cannabis Affect the Risk for Schizophrenia?

AV 2. The Effects of THC on the Brain (00:32)

Abbreviations are defined before the References

Dr Murray: THC is the psychoactive chemical in marijuana (AV 2).12

Dr Green: And, the THC content of cannabis has increased over time (AV 3).13

Dr Murray: Potency depends on the type of cannabis and its percentages of THC and CBD. While THC may be the major ingredient that increases the risk for psychosis, CBD may have antipsychotic properties. In the UK in the 1990s, old-fashioned resin (or hashish) would have had about 3% to 4% each of THC and CBD, whereas the engineered plants like sinsemilla or ‘skunk,’ which became the most often used form of cannabis by 2008, have up to 18% THC and almost no CBD.14

Dr Green: The percentage of CBD that happens to be in the plant may change the way people react to it. The problem is that we do not know exactly what type of marijuana people are using.

AV 3. Mean Δ-9 THC Content by Cannabis Type (00:41)

Data from Mehmedic et al13
Abbreviations are defined before the References

Dr Murray: One study14 found that 78% of first-episode patients, versus 37% of the control group, used high-potency cannabis (sinsemilla/skunk). Those with first episode psychosis were also 2 times more likely to have smoked cannabis for more than 5 years and 6 times more likely to be daily users.

It will be a while before proper longitudinal studies on high-potency cannabis are conducted. Tracking the concentration of cannabis is complicated because it requires testing blood levels, and nobody has done that.

What is the Risk When Marijuana is Combined With Other Substances?

Dr Murray: A portion of cannabis users also take other drugs, such as amphetamines or cocaine. For instance, in a sample8 of cannabis users with a first episode of psychosis, 73% had also used other drugs.

A recent cohort study15 in California found that methamphetamine use alone increased the risk of schizophrenia as much as cannabis did. But, the longitudinal study10 in Dunedin, New Zealand found that the risk was specific to cannabis use and not the use of other drugs.

Dr Kane: Does concurrent use of marijuana and alcohol change the risk of developing psychosis?

Dr Murray: A study16 in Scotland found that both alcohol and cannabis use were associated with brain changes and an increased risk of psychosis for those who already had a high genetic risk of schizophrenia. Perhaps, having a family history of schizophrenia may enhance the detrimental effects of alcohol and cannabis on the brain.

Does Stopping Cannabis Use Have Any Effect?

Dr Kane: Is anything known about what happens to the risk of schizophrenia if young people stop smoking cannabis? For example, if young people used cannabis for X number of years, stopped, and then remained drug-free for X number of years, are they still at increased risk of developing psychosis?

Dr Murray: I do not think anybody has done a long-term follow-up study on the risk of psychosis in people who smoke, say, until age 20 years and then stop. But, a study17 in Spain followed patients for 8 years after their first episode of psychosis. Symptom differences between those who stopped and those who did not stop using cannabis were not apparent during short-term follow-up. However, long-term follow-up found a reduction in negative symptoms and a better functional outcome in those who had stopped.

Dr Evins: Like cigarette smoking, people have to stick with abstinence for a while to see an effect.

How Could Legalizing Marijuana Affect Adolescents?

Dr Evins: The idea of legalizing marijuana may give the message to young people that it is safe.

Dr Green: The term medical marijuana makes it sound like a therapeutic agent, which may encourage more young people to use it.

AV 4. 12th-Grade Students’ Perceived Risk and Annual Use of Marijuana (00:24)

Data from University of Michigan News Service18

Dr Evins: In US high schools, I talk about tobacco use, which the students perceive as harmful, but they do not see marijuana use the same way (AV 4).18

Dr Green: Although legalization is a complex sociopolitical question, when focusing on the psychiatric aspects, we all agree that there are serious risks with cannabis use for at least some adolescents.

Conclusion

Many young people may not think using marijuana is harmful, but studies show that cannabis use does increase the risk of developing schizophrenia in vulnerable young people, especially if they start using marijuana before 18 years of age or become heavy users. Clinicians can screen patients for marijuana use and ascertain other risk factors for schizophrenia based on their family history, social and behavioral problems, and environmental factors. While the majority of young people will not develop schizophrenia, those most vulnerable to psychosis must be cautioned that using marijuana increases their risk.

Clinical Points

 

  • Recognize patients who may be vulnerable to psychotic disorders through their family history, social and behavioral problems, and environmental factors
  • Ask children and adolescents about marijuana use
  • Discuss the risks of marijuana use with child and adolescent patients and their parents
  • Warn patients with psychotic disorders to avoid marijuana use

 

Abbreviations

CBD = cannabidiol
COMT = catechol-O-methyltransferase
THC = ∆-9-tetrahydrocannabinol

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References

  1. O'Connell ME, Boat T, Warner KE, eds. Preventing Mental, Emotional, and Behavioral Disorders Among Young People: Progress and Possibilities. Washington, DC: National Academies Press; 2009. PubMed
  2. Tandon N, Montrose D, Shah J, et al. Early prodromal symptoms can predict future psychosis in familial high-risk youth. J Psychiatr Res. 2012;46(1):105–110. PubMed
  3. 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(10):1117–1127. PubMed
  4. Di Forti M, Iyegbe C, Sallis H, et al. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users [published online ahead of print July 23, 2012]. Biol Psychiatry. doi:10.1016/j.biopsych.2012.06.020. PubMed
  5. Mittal VA, Ellman LM, Cannon TD. Gene-environment interaction and covariation in schizophrenia: the role of obstetric complications. Schizophr Bull. 2008;34(6):1083–1094. PubMed
  6. Gilmore JH. Understanding what causes schizophrenia: a developmental perspective. Am J Psychiatry. 2010;167(1):8–10. PubMed
  7. Rey JM, Martin A, Krabman P. Is the party over? cannabis and juvenile psychiatric disorder: the past 10 years. J Am Acad Child Adolesc Psychiatry. 2004;43(10):1194–1205. PubMed
  8. Barnes TR, Mutsatsa SH, Hutton SB, et al. Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry. 2006;188(3):237–242. PubMed
  9. Fergusson DM, Horwood LJ, Ridder EM. Tests of causal linkages between cannabis use and psychotic symptoms. Addiction. 2005;100(3):354–366. PubMed
  10. Arseneault L, Cannon M, Poulton R, et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325(7374):1212–1213. PubMed
  11. Zalesky A, Solowij N, Yücel M, et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012;135(7):2245–2255. PubMed
  12. National Institute on Drug Abuse. DrugFacts: is marijuana medicine? http://www.drugabuse.gov/publications/drugfacts/marijuana-medicine. July 2012. Accessed November 19, 2012.
  13. Mehmedic Z, Chandra S, Slade D, et al. Potency trends of Δ9-THC and other cannabinoids of confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. 2010;55(5):1209–1217. PubMed
  14. Di Forti M, Morgan C, Dazzan P, et al. High-potency cannabis and the risk of psychosis. Br J Psychiatry. 2009;195(6):488–491. PubMed
  15. Callaghan RC, Cunningham JK, Allebeck P, et al. Methamphetamine use and schizophrenia: a population-based cohort study in California. Am J Psychiatry. 2012;169(4):389–396. PubMed
  16. Welch KA, McIntosh AM, Job DE, et al. The impact of substance use on brain structure in people at high risk of developing schizophrenia. Schizophr Bull. 2011;37(5):1066–1076. PubMed
  17. González-Pinto A, Alberich S, Barbeito S, et al. Cannabis and first-episode psychosis: different long-term outcomes depending on continued or discontinued use. Schizophr Bull. 2011;37(3):631–639. PubMed
  18. Marijuana use continues to rise among US teens, while alcohol use hits historic lows [news release]. Ann Arbor, MI: University of Michigan News Service; December 14, 2011. http://www.monitoringthefuture.org/pressreleases/11drugpr_complete.pdf. Accessed November 19, 2012.