Risk factors for the onset of dependence and chronic psychosis due to cannabis use: Survey of patients with cannabis‐related psychiatric disorders

Abstract Aim The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. Methods We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis‐related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross‐sectional interview surveys conducted by each patient's attending psychiatrist. Results For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9‐tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late‐onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. Conclusion The onset of cannabis dependence was related to long‐term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis.


| INTRODUC TI ON
Major changes in cannabis policies have recently occurred in a number of countries worldwide. For example, the Canadian government legalized cannabis for recreational use in October 2018. 1 In the United States, cannabis for recreational use has been legalized in eight states, and the use of cannabis for medical purposes is already legal in 25 states, 2 although the federal government does not tolerate cannabis use. These international trends are expected to have an impact on Japanese cannabis policies in the near future. Therefore, the health problems resulting from cannabis use, including the onset of dependence and psychiatric illness, are an important public health concern.
Although animal and human research has confirmed that cannabis is an addictive drug, 3 only a limited number of people who use cannabis become addicted. 4 A large-scale epidemiological study conducted in Europe 5 reported that the proportion of people who use cannabis and become addicted was significantly lower than the number of individuals who become addicted to nicotine, alcohol, or cocaine after use. From the perspective of dependence prevention, it is important to elucidate the risk factors for the onset of dependence due to cannabis use. In previous studies conducted in various countries, the frequency and duration of cannabis use, the Δ9-tetrahydrocannabinol (THC) content of the cannabis product used, [6][7][8] family history of substance dependence, [9][10][11] presence of psychological distress before starting to use cannabis, 12 and cannabis use early in life 11,13 were identified as risk factors for the onset of cannabis dependence.
Moreover, chronic psychosis, a psychiatric illness that can be difficult to differentiate from schizophrenia, is reported to be related to cannabis use. This association was reported for the first time by Andreasson et al in a longitudinal study of Swedish conscripts in the late 1980s. 14 Since then, numerous studies have reported similar findings, [14][15][16][17][18][19][20][21][22][23][24][25] and it has been estimated that 6.2% to 24% of all psychiatric illnesses would not have occurred if the patient had not used cannabis. 26 However, the number of people who use cannabis and develop a psychiatric illness is very small. Further, a study in the United Kingdom did not support a relationship between cannabis use and chronic psychosis, reporting that the national prevalence of schizophrenia remained unchanged or slightly decreased over a period in which the proportion of people who used cannabis increased. 27 To date, identified risk factors for the onset of psychiatric illness related to cannabis use include a family history of psychiatric disorders, 28,29 cannabis use early in life, 13 use of cannabis products with a high THC content, 30 and the use of cannabis to alleviate the symptoms of psychiatric disorders. 31 Whether these international findings apply to Japan, which has unique laws, regulations, and a national lifetime prevalence of cannabis use, is unclear. Only a small number of previous studies have examined cannabis-related psychiatric disorders in Japan, and all of these studies were case reports with a maximum of six cases. [32][33][34][35][36] Furthermore, these studies all focused on describing the clinical pre- Therefore, the current study was conducted to elucidate the risk factors that affect the onset of dependence and chronic psychosis due to cannabis use in a relatively large number of patients with cannabis-related disorders. Moreover, we investigated the risk factors identified in previous studies, including clinical genetic factors, the impact of psychiatric disorders present prior to cannabis use, the starting age of cannabis use, duration and frequency of cannabis use, cannabis products (THC content) used, and the impact of the combined use of other psychoactive substances.

| Subjects
We selected nine mental health hospitals with more than 100 re- clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis.

Conclusion:
The onset of cannabis dependence was related to long-term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis.

K E Y W O R D S
cannabis, chronic psychosis, dependence, risk factor, use disorder among the 1264 mental health hospitals nationwide that participated in the 2018 Nationwide Mental Hospital Survey on Drug-Related Psychiatric Disorders (hereinafter referred to as the "NMH Survey") 38 . In the NMH Survey, these nine mental health hospitals reported 1328 cases of cannabinoid-related psychiatric disorders, which accounted for approximately half (48%) of all 2767 cases of drug-related psychiatric disorders. Each of the facilities had a specialized treatment system for drug dependence.
The patients were all adults who (a) fell under the ICD-10 classification "F12-Mental and behavioral disorders due to use of cannabinoids," (b) underwent treatment as an outpatient or inpatient at one of the nine psychiatric hospitals during the 3-month period from October to December 2019, and (c) provided consent to participate in this study.

| Survey procedure
For information collection, we employed a cross-sectional method, using interviews conducted by the attending psychiatrists at the study sites. During therapy sessions, each attending psychiatrist directly asked patients who met the inclusion criteria questions after they had given verbal consent. Patient responses were entered into the survey sheet after judgment by the attending psychiatrists, who referred to the information provided in the patient's medical records.
Completed survey sheets were anonymized, sent to the lead author by mail, and then analyzed.
This study was conducted after approval by the ethics committee of the National Center of Neurology and Psychiatry (approval number A2019-060), the principal study facility, and subsequently by the ethics committees of the other eight psychiatric hospitals.

| Examined items
As examined items, in addition to general characteristics such as age, biological sex, academic background, and current employment and occupational status (employed or unemployed), items related to the following two areas were assessed:

| Psychiatric items
• Clinical genetic factors: Family history of psychiatric disorders, substance dependence/addiction behavior, and suicidal behavior (suicide attempts and completed suicide). Subjects were asked about their second-degree family history, and "suspected" cases with no treatment history were considered to indicate a family history.
• ICD-10 diagnostic subclassification "F12-Mental and behavioral disorders due to use of cannabinoids" at the time of the survey • Diagnostic classification of comorbid psychiatric disorders according to the main ICD-10 category at the time of the survey, and the temporal relationship between onset and cannabis use.

| Items related to the history of cannabis use
• Age at the time of first cannabis use • Age at the time of final use: In this study, the number of years of cannabis use was calculated automatically as follows: Age at the time of final use minus age at the time of first use. When studying drug dependence, the duration of illicit drug use can be difficult to calculate because drug use is often irregularly interrupted by detention or imprisonment, and self-reported information can be unreliable. Some studies neglected duration and focused instead on the age when drug use started, 11,13 while others simply counted the duration using the above method. 39 In the present study, we adopted this method in addition to collecting the age at which drug use started.
• Cannabis products used (four categories: dried [herbal] cannabis, cannabis resin, liquid cannabis, and other): We examined whether the subject had used cannabis products that contain high levels of THC such as cannabis resin and liquid cannabis. We adopted this dichotomic classification system based on previous findings.
Particularly, a seminal study using gas chromatography demonstrated that THC content was highest in liquid products and lowest in herbal products. 40 Further, a recent study conducted in Japan found that resin products termed "cannabis wax" contained 50 times more THC than general dry cannabis. 41 These findings suggest that resin and liquid products may contain relatively high levels of THC compared with dried/herbal products.

| Statistical analysis
Based on the collected information, we conducted binomial logistic regression analysis of all target subjects using two ICD-10 diagnoses (current "dependence syndrome," and "residual and late-onset psychotic disorder," which refers to a state of chronic psychosis caused by cannabis use) as dependent variables, and then examined the factors associated with these two diagnoses. We selected the following as independent variables: "family history of psychiatric disorders, substance dependence/addiction behavior, and suicidal behavior," "onset of comorbid psychiatric disorder before starting to use cannabis," "age at the time of first cannabis use," "number of years of cannabis use," "use of cannabis products other than dried cannabis," and "combined use of other psychoactive substances," which were identified as risk factors for the onset of dependence and chronic psychosis due to cannabis use in previous studies. We then conducted univariate and multivariate analysis of each of these variables.
All statistical analysis was conducted using SPSS ver. 26 (IBM), and the significance level was set at <5%.

| RE SULTS
A total of 73 patients who underwent treatment at the nine mental health hospitals during the survey period fell under the category ICD-10 "Mental and behavioral disorders due to use of cannabinoids," and 71 of these patients provided consent to participate in this study (consent rate: 97.3%). Table 1 shows the subject characteristics. The mean age was Regarding comorbid psychiatric disorders confirmed at the time of this survey, 31 subjects (43.7%) were confirmed to have some sort of comorbid psychiatric disorder. The most common was "F3: Mood disorder," which was identified in 13 subjects (18.3%), followed by "F2: Schizophrenia, schizotypal, and delusional disorders" in eight subjects (11.3%), "F6: Disorders of adult personality and behavior" in six subjects (8.5%), "F8: Disorders of psychological development" in four subjects (5.6%), "F5: Behavioral syndromes associated with physiological disturbance and physical factors" in three subjects (4.2%), "F4: Neurotic, stress-related, and somatoform disorders" and "F9: Behavioral and emotional disorders with onset usually occurring in childhood and adolescence" in two subjects (2.8%) each, and "F0: Organic, including symptomatic, mental disorders" and "F7: Mental retardation" in one subject (1.4%) each. Regarding the earliest onset of comorbid psychiatric disorders, onset in 16 subjects (22.5%) occurred before they started to use cannabis. Regarding the rate of usage in the period in which cannabis use was most frequent, "≥4 days per week" was the most common response, given by 45 subjects (63.4%), followed by "1 day per week to <4 days per week" in 20 subjects (28.2%), "once per month to <1 day per week" in four subjects (5.6%), and "less than once per month" in two subjects (2.8%).

| D ISCUSS I ON
To the best of our knowledge, the current study examined the larg- The present data reveal an association between the absence of comorbid psychiatric disorders prior to cannabis use and chronic psychosis due to cannabis use. This finding could have resulted from several factors. In the case of patients who had some type of psychiatric disorder before starting to use cannabis, chronic psychosis was not considered to be after effect of cannabis use (residual and late-onset psychotic disorders), but instead, as a disease state in which latent schizophrenia was induced by cannabis use, and thus was counted as a comorbid psychiatric disorder. In that sense, the finding that only a small number of patients who were diagnosed with residual and late-onset psychotic disorders had comorbid psychiatric disorders before starting to use cannabis was an expected result given the definition of the diagnostic criteria and disease state.
In contrast, it is difficult to explain the observed association between chronic psychosis due to cannabis use and no history of using cannabis products with a high THC content. A mentioned above, the current findings indicate that the frequency and duration of exposure to THC-the constituent responsible for the psychotropic activity of cannabis-were not associated with the onset of chronic psychosis. In that context, it is unsurprising that the use of cannabis products with a high THC content was not related to the onset of chronic psychosis. These suggest that the onset of cannabis-related chronic psychosis may be more influenced by individual/ constitutional factors, including clinical genetic factors and those that precede the onset of comorbid psychiatric disorders, than the total amount of THC exposure, although we found no associations between individual/constitutional factors and chronic psychosis in this study.
The reason why a significant negative association was observed between the use of high THC-containing products and chronic psy- Therefore, further investigation should be required in this respect. TA B L E 3 Logistic regression analysis regarding the current diagnosis of "F12.2 Dependence syndrome due to use of cannabinoids" The current study has several limitations that should be considered. First, the "number of years of cannabis use" was automatically calculated from the difference between the "age at the time of final cannabis use" and the "age at the time of first cannabis use." Periods of voluntary drug abstinence and periods of forced drug abstinence while serving a prison term were not considered.
Therefore, the number of years of cannabis use and the total amount of cannabis used may not be positively correlated. Second, the ICD-10 "Residual disorders and late-onset psychotic disorder" is a heterogenic group including rare psychiatric cannabis-related conditions in clinical practice, such as flashbacks, organic personality disorder, organic mood disorder, and dementia, in addition to chronic psychosis. Therefore, the risk factors identified in this study may be inconsistent with those of purely chronic psychosis. Despite the limitations described above, the current study represents an important contribution as the only study of its kind in Japan. We examined the largest sample of patients to date with cannabis-related psychiatric disorders in Japan to investigate the onset of dependence and chronic psychosis due to cannabis use while considering clinical genetic factors, preceding psychiatric issues, and the mode of cannabis use.
The current study examined risk factors for the onset of dependence and chronic psychosis due to cannabis use in 71 patients with cannabis-related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. The results suggested that the onset of dependence may be related to long-term cannabis use and the use of cannabis products with a high THC content. However, regarding the onset of chronic psychosis, no association was observed for total intake of THC (including duration and frequency of use), or for psychiatric vulnerability (including clinical genetic factors and the presence of preceding psychiatric disorders). These findings indicate that the onset of chronic psychosis is related to unknown factors.

CO N FLI C T O F I NTE R E S T
We declare that we have no conflicts of interest in relation to this study.

AUTH O R CO NTR I B UTI O N S
TM, TK, and TS designed the study, and TM drafted the main manuscript. TM, DF, TU, and MM analyzed the data, and KO and YT reviewed previous studies. All the authors collected data and drafted tables and parts of the manuscript.

Approval of the research protocol by an Institutional Reviewer
Board: This study was conducted after approval by the ethics committee of the National Center of Neurology and Psychiatry (approval number A2019-060), the principal study facility, and subsequently by the ethics committees of the other eight psychiatric hospitals.

I N FO R M ED CO N S ENT
In addition to giving public notice regarding the implementation of the study, the candidate was given a face-to-face explanation of the study and verbal consent was obtained.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.