Health and Medicine: General

Critical Factors Involved in the Relationship Between Cannabis and Schizophrenia

By Carly Cheung, Microbiology, ’17

Author’s Note:

“I wrote this piece for my UWP 104F: ‘Writing in the Health Professions’ class with Professor Walsh in Winter 2016. Our assignment was to examine a health related research question and explore the subject in a quarter-long research and synthesis process. I decided to write about Schizophrenia because I realized that I knew close to nothing accurate about people with mental health illnesses. Lack of understanding of the disease can contribute to stigmatization of these patients and cause further psychological harm. On my way to demystifying Schizophrenia, one of the most researched relationship I found was that of Marijuana and Schizophrenia. Throughout this process, I not only gained valuable knowledge on this topic, but I also learned to appreciate the various methods scientists developed to study the mechanism of this multi-layered and abstract disease.”

Abstract

The high prevalence of Schizophrenic patients with the comorbidity of cannabis-dependency disorder prompted researchers to investigate the relationship between cannabis and schizophrenia. The purpose of this literature review is to examine the current research on various factors that are significant in this association. The paper will look into retrospective studies that compare and contrast the two groups: schizophrenic patients with cannabis-dependency disorder and schizophrenic patients without cannabis-dependency disorder. Furthermore, I will examine studies that analyze the effects of cannabis on the cognition of adults with schizophrenia and cannabis-dependency disorder, as well as studies that explore the effects of cannabis on adolescents and its relation to schizophrenia. Significant factors found to be involved in this relationship are age, gender, genetic predisposition, and cannabis consumption behaviors.

Introduction

Schizophrenia spectrum disorder is a debilitating chronic mental illness that alters one’s emotional, psychological, and cognitive foundations. It gives rise to hallucinations, delusions, mania, reduced expression of feelings and pleasure, poor decision making skills, impaired working memory, and unusual thought content. Often times, schizophrenic patients acquire other illnesses, such as cardiovascular diseases, diabetes, depression, bipolar disorder, multiple personality disorder, and drug addiction- the reason for which is another large topic of research. The cause of Schizophrenia is unknown and, as is the case for many mental illnesses, diagnosis relies on the appearance of particular symptoms. This questions the accuracy of the diagnostic criteria and demonstrates the lack of knowledge the medical community retains on this disease. Interestingly, schizophrenic patients present a median lifetime cannabis use disorder rate of 27.1%, as compared to the general population lifetime cannabis disorder rate of 10%. Cannabis-use disorder or cannabis-dependency disorder is characterized by an unhealthy pattern of usage of cannabis despite the harmful disturbances on daily activities and the consequences of physical and mental distress. This high correlation between cannabis and schizophrenia captures the attention of many researchers. In current literature, studies are conducted to answer three questions: (1) Does cannabis usage induce schizophrenia? (2) If so, is cannabis-induced schizophrenia a distinct disorder of its own? (3) Does the onset of schizophrenia draw patients to consume cannabis? My literature review will attempt to analyze in depth the most important factors involved in the relationship between schizophrenia and cannabis, as well as attempt to answer the three big questions in schizophrenia research today.

Retrospective Studies of Schizophrenic Patients with Cannabis-dependence disorder and Schizophrenic Patients without Cannabis-dependence disorder

Comparing and contrasting the variables associated with the schizophrenic patients who are lifetime cannabis users and those who are not is a logical starting point to begin analysis of the role cannabis plays in schizophrenia. Helle et. al. (2016) considered the factors: family history of psychosis, gender, age of onset of Schizophrenia, and type of substance consumed. A large heterogeneous sample of 1,119 patients in the age range of 18-65 were drawn from three clinical sites in Norway. They were clinically diagnosed with Schizophrenia using the diagnostic test DSM-IV. This manual allows health professionals to take into consideration multiple factors and severity of the factors to diagnose patients effectively. Family history of psychosis, lifetime substance use, and age of onset of schizophrenia information were obtained through patient interviews. Age of onset of schizophrenia is determined by first psychotic episode, either reported by patients or determined by the patient’s first visit to a clinical psychiatrist. Using information from interviews and urine samples, the participants were diagnosed with substance use disorders. The substance-use group included participants who abused, were dependent on, had lifetime registration of, or had positive results on urine tests for one of the following substances: cannabis, amphetamines, cocaine, hallucinogens, and opiates. The abstinent group never used any of these substances. A thorough comparison of the two groups revealed that there were more males in the substance group, 67.8%, as compared to the abstinent group of 53.5%. The substance group was comprised of younger participants with lower average years of education, and a shorter mean duration of illness. Cannabis is the only substance found to be significantly associated with the age of onset of Schizophrenia; approximately a three years earlier age of onset of psychotic symptoms is seen in schizophrenic patients who are cannabis-dependent.

Sarzzazin et. al. (2015) conducted a similar study with more specific groups but fewer participants. The participants consisted of 171 schizophrenic patients from a hospital in France; they were grouped into “Pre-onset Cannabis-use disorder” group (Pre-onset CUD) or “No pre-onset group” (No Pre-onset CUD). Patients who stated that their usage of cannabis started at or before the onset of schizophrenia are in the pre-onset group and all other schizophrenic patients with co-morbidity of CUD were classified in the No Pre-onset CUD group. Through comparisons, it was found that the Pre-onset CUD group was predominately male (67.1%), however, there was no difference in the mean age of onset of schizophrenia (both 23.7 years of age) or difference in types and magnitude of symptoms or magnitude of symptoms.

Mane et. al. (2015) compared and contrasted demographic, family history, symptoms, and gender in 119 first psychotic episode schizophrenic patients from ages 18-35 who were cannabis users and those who were not. First psychotic episode schizophrenic patients refer to those that have only experienced psychotic symptoms once. The patients in the cannabis-users group used cannabis at least weekly in the previous six months. Additionally, the participants filled out questionnaires specifying their reasons for cannabis use. There was no difference in symptoms found between cannabis users and non-cannabis users. However, cannabis users had an earlier onset of psychosis and were predominately male. The reasons for cannabis use in schizophrenic patients are largely to deal with hallucinations, suspiciousness, boredom, depression, or to alleviate medication side effects. This study supports the hypothesis that schizophrenia induces patients to seek cannabis usage.

Helle et. al. and Sarzzazin et. al, examined factors that are difficult to determine correctly. The methods used to determine age of onset of schizophrenia and history of psychosis were based on patients’ memory quality or on access to medical notes and interviews. However, asking patients to recollect information from memory is not very accurate. Inaccuracy  in methods may contribute to the discrepancy between Helle et. al. finding that cannabis increases onset of schizophrenia by three years and Sarzzazin finding no correlation between cannabis and age of onset of schizophrenia. Furthermore, there may be information about family history that researchers do not have records of. With these limitations in mind, all three studies found no difference in family history of psychosis between the two groups, suggesting that genetics do not play a role in the onset of schizophrenia. Additionally, there were no differences in demographic and clinical characteristics. This does not support the hypothesis that cannabis-induced schizophrenia is its own clinical entity. Helle et. al, Sarzzazin et. al, and Mane et. al. found that cannabis-using groups are most likely to be male and younger than the non-cannabis users. Relationships found in these studies could be identified as correlation and not causation because there is no clear cause-effect relationship examined.

While the previous studies mentioned in this literature review determined possible correlations between cannabis usage and schizophrenia, Kelley et. al. (2016) determined a causation relationship; in this retrospective study, marijuana use in the premorbid period was examined. A total of 247 English-speaking participants between ages 18 and 40 were used in this study. Marijuana, alcohol, and tobacco use were recorded based on how many joints, drinks, and cigarettes were used per month. Interviews were conducted with each patient and two other family members to determine the month of onset of psychotic symptoms. Subsequently, a precise number of the three substance used were determined in the period before psychotic symptoms began, the premorbid period, for each participant. The study found that certain behaviors during the premorbid period correlated with an increase in psychosis. Males, again, were found to be more prevalent in all substance groups. An increase in use of marijuana was associated with an increase in rate of psychosis. Daily use during pre-prodromal period approximately doubles the rate of progression to schizophrenia. Any increase in use during the premorbid period increases the rate of onset of schizophrenia. Specifically, escalation of marijuana usage in the five years premorbid period causes an earlier onset of schizophrenia.

The temporal link found between usage of marijuana and onset of schizophrenia shows that the usage of marijuana during the premorbid period is not the most important. Rather, the increase of dosage during that period is the most predictive of an earlier onset of schizophrenia. However, it is important to note that in this study, cannabis was found to increase the rate of onset of schizophrenia, not induce the onset of the disorder itself. This discovery explains the lack of difference found in age of onset of schizophrenia between pre-onset CUD group and no pre-onset CUD group in Sarzzazin et. al. Because the study did not take into account the amount of cannabis usage during the time before the onset of schizophrenia, no differences in the groups’ age of onset were seen.

Effects of cannabis on Cognition of Adults with Schizophrenia

The study conducted in Power et. al. (2015) classified schizophrenic patients into three groups: cannabis non-users (CN), cannabis- users (CU), and cannabis dependency (CD) and administered two cognitive assessment tests. The National Adult Reading Test Revised was used to assess the cognitive ability prior to illness onset and the Digit Symbol Coding Test assessed the patients’ current cognitive abilities. Demographic and clinical differences between the groups were examined after accounting for confounding variables. No difference in the results of the tests was found between the groups, revealing that cannabis has no effect on the Intelligent Quotients of the schizophrenic patients.

Risk-taking is an important function in executive cognitive abilities and correlates with one’s ability to make decisions. People with schizophrenia and comorbid of cannabis dependence have been observed to possess altered risk-taking abilities. This study analyzes participants’ risk taking abilities with a virtual lab experiment and two questionnaires. The Balloon Analog Risk Task (BART) is a simulation where participants are to assess when to pump a virtual balloon, given caution to not pop the balloon. Money was given to the participants for each pump, but once the balloon pops, the money accumulated diminishes as well. The Risk Perception Questionnaire and the Self Mastery Scale allow the participants to analyze their own locus of control. Schizophrenic patients without cannabis-dependent disorder displayed the least amount of risk taking among the three groups. Patients with schizophrenia and co-occurring cannabis dependence have a unique pattern of risk taking that is intermediate between people with schizophrenia and people who are cannabis dependent. (Fischer, 2015)

While Power et. al found that the intelligent quotient in adults are not affected by cannabis usage, the study in Fischer et. al. shows that there are cognitive differences between schizophrenic patients and schizophrenic patients with cannabis dependence disorder. The difference in cognitive results seen in the two studies might be because cannabis induces an effect on different cognitive domains of the brain, which are differentiated by the tests determining participants’ intelligence quotient and the tests assessing participants’ risk-taking abilities. The results from the two studies indicate a possible weak correlation between cannabis and cognition in schizophrenic patients.

Early Cannabis use Impact on Adolescent Brain

Perhaps the most direct way to analyze cannabis’ effects on people is a direct injection of cannabis into rats and then note the immediate results. In this experiment, Renard and her research team injected adult and adolescent rats with the psychoactive component in marijuana, delta-9-tetrahydrocanabinol (THC). They observed whether the injection increased schizophrenic symptoms, as compared to control adult and adolescent rats with no injections. Willingness of the rats to interact with others determined the variable for social motivation and social cognition. Furthermore, anxiety behaviors were observed by examining rats’ startle reflex to white noise and by placing rats in a box filled with light and observing the time it takes for the rats to leave the dark box and enter the light box because rats are naturally display adverse behaviors towards light. Neural recordings placements were also done to examine the frequency of neuronal firing in the brain. Lastly, the protein extraction was conducted. THC injected adolescent rats spent less time with stranger rats, traveled shorter distances, and made fewer transitions from dark to light boxes, as well as spent more time doing so. An increase in frequency of neuronal firing in adolescent rat and a hyperactive dopamine pathway were found. In adolescent rats, there was a significant decrease in phosphorylated proteins, while a significant increase in phosphorylated proteins was observed in adult rats.

Similarly, many studies have found cannabis to have an effect on neurological development of adolescents, especially during the spike of testosterone in adolescent boys during puberty. In French et. al, (2015), magnetic resonance imaging (MRI) was used to observe the effects of cannabis on adolescent brains during age 14 and 18. They observed the cortical thickness of the brain and the amount of gray matter present. Participants were separated into 2 groups based on a self-report questionnaire about whether or not participants have consumed cannabis in their life. Lower cortical thickness and lower amounts of gray matter were seen in males with higher polygenic risk score who consumes cannabis regularly, beginning at an age as early as 16. This correlation was not seen in females with high-risk scores or males with low risk scores.

We can confidently conclude that adolescents are more sensitive to the effects of cannabis than adults. Not only do the behavioral changes seen in adolescent rats support the hypothesis of the significant effect cannabis has on the subjects, but the discovery of physically altered proteins through phosphorylation in the dopamine pathway further confirms this conclusion.Specifically, in human male adolescents who are genetically predisposed to schizophrenia and began usage of cannabis early in their lifetime, lower cortical thickness and a decrease in the amount of gray matter in the brain was observed. Both cortical thickness and gray matter are indicative of the cognitive functions of the participants. These studies provide solid evidence in support of the hypothesis that long-term exposure of marijuana in male adolescents may lead to neuropsychiatric-like symptoms such as anxiety, decreased social motivation and cognition, working memory dysfunction, and altered signaling pathways in the brain.

Conclusion

The relationship between cannabis and schizophrenia still remains controversial. Understanding mental illnesses such as schizophrenia poses a challenge to health professionals because the symptoms cannot be easily measured and examined without relying on subjective accounts from patients. Despite lack of objective tools to examine factors involved in the association between cannabis and schizophrenia, researchers manage to conduct sound experiments, although each carry its own limitations. Retrospective analysis provided incongruous evidences of earlier onset of schizophrenia with cannabis-dependence disorder. However, when taking into account the specific amount of cannabis consumed in the prodromal period, it solidified a strong association between time of consumption and behavior of consumption to earlier onset of psychotic symptoms. While no difference in clinical symptoms were found between cannabis-dependence schizophrenic patients and schizophrenic users that were non-cannabis users, the larger amount of psychotic symptoms found in adolescent rats in comparison to adult rats provided a clue that age is an important factor to consider. More research on cannabis’ effects on adolescent brains revealed that genetically predisposed adolescent males who consumed cannabis regularly had a higher likelihood of jumpstarting the onset of the illness. Current literature does not support cannabis-induced schizophrenia as a separate entity, but the hypothesis of using cannabis as self-medication was supported several times. From the evidence proposed, cannabis consumption does not directly cause the onset of schizophrenia, but well-conducted studies do suggest cumulative cannabis consumption in the premorbid period does induce an earlier onset of schizophrenia-like symptoms in genetically predisposed male adolescents. Specific effects of cannabis on human adolescents reinforce this association. More studies will need to be conducted to further explore if the relationship between cannabis and schizophrenia is actually a causation relationship and to provide insight for possible treatments and cures for Schizophrenia.

References

Fischer, B.F., McMahon, R.M., Kelly, D.K., Wehring, H.W., Meyer, W.M., Feldman, S.F., Carpenter, W.C., Gorelick, D.G. (2015). Risk-taking in Schizophrenia and Controls with and Without Cannabis Dependence. Schizophrenia Research, 161, 471-477, doi: 10.1016/j.schres.2014.11.009.

French, L.F., Gray, C.G, Leonard, G.L., Perron, M.P., Pike, B.P., Richer, L.R., Seguin, J.S… (2015). Early cannabis use, polygenic risk score for schizophrenia, and Brain Maturation in Adolescence. American Medical Association, 72, 1002-1011, doi: 10.100/jamapsychiatry2015.1131.

Helle, S.H., Ringen, A.R., Melle, I.M., Larsen, T.L., Gjestad, R.G., Johnsen, E.J., Lagerberg, T.L., Andreassen, O.A., Kroken, R.K., Joa, I.J., Hegelstad, W.H., Loberg, E.L. (2016). Cannabis use is associated with 3 years earlier onset of Schizophrenia spectrum disorder in a naturalistic, multi-site sample (N=1119). Schizophrenia Research, 170, 217-221, doi: 10.1016/j.schres.2015.11.027.

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Mane, A.M., Fernandez-Exposito, M.F., Berge, D.B., Gomez-Perez, L.G., Sabate, A.S., Toll, A.T., Diaz, L.D., Diez-Aja, C.D., Perez, V.P. (2015). Relationship Between Cannabis and Psychosis: Reasons for Use and Associated Clinical Variables. Psychiatry Research, 229, 70-74, doi:10.1016/j.psychres.2015.07.070

Power, B.P., Dragovic, M.D., Badcock, J.B., Morgan, V.M., Castle, D.C., Jablensky, A.J., Stefanis, N.S. (2015). No Additive Effect of Cannabis on Cognition in Schizophrenia. Schizophrenia Research, 126, 241-251, doi: 10.1016/j.schres.2015.06.026.

Renard, J.R., Rosen, L.R., Loureiro, M.L., Oliverira, C.O., Schmid, S.S., Rushow, W.R., Laviolette, S.L. (2016). Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex. Cerebral Cortex, 26, 1-14, doi: 10.1093/cercor/bhv335

Sarrazin, S.S., Louppe, F.L., Doukhan, R.D., Schurhoff, F.S. (2015). A Clinical Comparison of Schizophrenia with and Without Pre-onset Cannabis use Disorder: A Retrospective Cohort Study using Categorical and Dimensional Approaches. Annals of General Psychiatry, 2015. doi: 10.1186/s12991-015-0083-x