Marijuana and Psychosis

A 2015 literature review found that synthetic cannabis may cause more frequent and more severe negative effects compared to natural cannabis, and psychosis and psychosis-like conditions seem to occur relatively often following the use of synthetic cannabis. Prolonged psychotic symptoms from synthetic cannabis have been reported for some patients. Psychotic periods associated with synthetic cannabis have been found to vary between 1 week and 5 months.

The most common cognitive effect of synthetic cannabinoids observed in studies is impairment of attention, concentration, memory, and operational skills. While these effects are generally seen during intoxication, these symptoms can persist beyond the time of acute intoxication and withdrawal.

Delusions and hallucinations, agitation, disorganization of thought, confusion, and impaired speech have been documented across studies to be associated with use of synthetic cannabinoids.

The National Institute of Health cites a study by Khan and Akella, Cannabis-Induced Bipolar Disorder with Psychotic Features (2009 Dec, Psychiatry; 6(12): 44-48.  The introduction section of the article includes the following:

The role of cannabis in psychiatric illnesses has been an area of interest. Epidemiological studies have shown that as the frequency of cannabis abuse increases, so does the risk for a psychotic disorder such as schizophrenia. Studies have also shown that cannabis is the most commonly abused drug among those diagnosed with bipolar disorder. Looking at the pharmacokinetics of the psychoactive agent ∆9-tetrahydrocannabinol (∆9-THC), its effects are perceptible within minutes. ∆9-THC is extremely lipid soluble and can accumulate in fatty tissues reaching peak concentrations in 4 to 5 days. It is then slowly released back into the body, including the brain, reaching high concentrations in the neocortical, limbic, sensory, and motor areas. The tissue elimination half-life of ∆9-THC is about seven days, and absolute elimination of a single dose may take up to 30 days. Interestingly enough, the plasma levels of ∆9-THC poorly correlate with urine levels, making the urine toxicology screen a wholly unspecific test.

Cannabis intoxication can lead to acute psychosis in many individuals and can produce short-term exacerbations of pre-existing psychotic diseases. Cannabis use also causes symptoms of depersonalization, fear of dying, irrational panic, and paranoid ideas, which coincide with acute intoxication and remitted quickly. In one survey, it was reported that 15 percent of cannabis users identified psychotic-like symptoms, the most common being hearing voices or having unwarranted feelings of persecution. What research has failed to show is if cannabis use is a consequence or cause of psychiatric disorders. Based on research reviews, looking at the connection between cannabis and psychosis, two hypotheses have been developed. The first hypothesis is that cannabis use causes psychotic symptoms in an otherwise healthy individual that would not have occurred with abstinence. The second hypothesis is that cannabis use may precipitate psychosis in individuals who are predisposed to acquiring a psychotic disorder. Only two case studies have reported prolonged depersonalization after cessation of cannabis use. Symptoms experienced during drug-free periods are rarely reported.

The role of cannabis in causing bipolar disorder is not well documented. Epidemiological studies have shown that bipolar disorder has the highest rate of substance abuse comorbidity of any axis I disorder. The Epidemiologic Catchment Area (ECA) study found that 41 percent of patients with bipolar disorder had a comorbid substance use with cannabis being the most frequently abused. Cannabis abuse prior to development of bipolar disorder has a significant effect on first-episode mania and on the course of the disease. Another study reported that using cannabis at baseline can significantly increase the risk for manic symptoms during follow up.

Recent advances in cannabinoid receptors and endogenous ligands have renewed interest in the mechanisms by which cannabis can cause major psychiatric disorders. It is now recognized that the endocannabinoid system represents a new signaling process in the nervous system that regulates neurotransmitter systems, energy metabolism, and immune function. Researchers now believe that cannabis consumption during critical phases of brain development can lead to a strong disturbance of the endocannabinoid system and ultimately cause an inappropriate hardwiring of the brain. Cannabis may play a role in the complex interactions involving dopamine, gamma aminobutyric acid (GABA), and glutamate transmission or other factors that cause psychotic disorders. However, the question remains as to why, in a general population of cannabis abusers, do only a small population exposed develop a psychiatric illness.

We present a unique case of a young college student, with no family history of any psychiatric illness, who presents with psychosis secondary to cannabis abuse. His psychosis persisted long after he stopped abusing cannabis, and he needed to be treated medically for new onset bipolar disorder with psychotic features. In the face of no known genetic predisposition, it is interesting that cannabis was his only trigger for psychosis, which warrants further study into understanding the exact mechanism that cannabis affects the neurotransmission at various receptors.

Gage and associates (2016) reviewed evidence from ten longitudinal studies examining the relationship between cannabis consumption and psychosis.  The researchers conclude:

The results from these longitudinal studies show a consistent pattern of association between cannabis and psychosis, which could be indicative of a causal relationship. (p. 549)

There are a number of facets of the evidence presented above that are consistent with a causal association between cannabis and psychosis. The longitudinal, case-control, and cross sectional studies conducted to date have, for the most part, found consistent evidence of an association, even after adjustment for covariates. Those that assessed a dose response relationship have found evidence for this. The experimental evidence showing that psychotic experiences occur during cannabis intoxication (1) indicates that cannabis has biological effects that could translate to chronic psychotic disorders. Neurobiological evidence on the effect of cannabis use, which includes dopaminergic, glutaminergic, and gamma aminobutyric acid activity modulation, are broadly consistent with the current understanding of neurobiology of psychotic disorders (55), as discussed in other articles in this issue.  There is also indirect evidence that supports causality. For example, a number of studies (12–14), although not all (16,23), found evidence for specificity of exposure, namely that associations between other drug use and psychosis are weaker than for cannabis. There is also some evidence of specificity of outcome (10,56) though this is not seen in all studies. (p. 553)

The authors conclude:

Although there is always uncertainty when observational studies are relied on for evidence of causation, there is a strong body of epidemiologic evidence to support the view that regular or heavy cannabis use increases the risk of developing psychotic disorders that persist beyond the direct effects of exogenous cannabinoids. . .  (p. 554)

Association Between Cannabis and Psychosis: Epidemiologic Evidence
Suzanne H. Gage, Matthew Hickman, and Stanley Zammit
2016 Society of Biological Psychiatry April 1, 2016; 79:549–556

Research on Cannibis-Induced Psychosis

Adverse reaction to marihuana.
Keeler, Martin H.
The American Journal of Psychiatry, 124(5), 1967. pp. 674-677.
Abstract:
Case reports of panic, gross confusion, depersonalization, depression, and paranoia following the use of marijuanain a student population are presented. These reports of adverse reaction are interpreted in the light of the expected reaction to the drug, other reports of adverse reaction, and the nature of the populations studied.

Long-term cannabis use: Characteristics of users in an Australian rural area.
Reilly, David, et al.
Addiction, Vol 93(6), Jun, 1998. pp. 837-846.
Abstract:
Investigated the characteristics and patterns of cannabis and other drug use among long-term cannabis users in an Australian rural area. The study involved 268 long–term cannabis users who had regularly used cannabis for at least 10 years. A structured interview schedule obtained information on: demographics, social circumstances, patterns of cannabis and other drug use, contexts of use, perceptions about cannabis and legal involvement. The mean age of the sample was 36 years and 59% were male. The median length of regular cannabis use was 19 years. Most used 2 or more times a week and 60% used daily, with a median of two joints per day. Two-thirds used cannabis in social settings and two-thirds grew cannabis for their own use. The most common reasons for using cannabis were for relaxation or relief of tension and enjoyment or to feel good. The most commonly reported negative effects were feelings of anxiety, paranoia, or depression, tiredness, lack of motivation and low energy and effects of smoke on the respiratory system. The majority drank alcohol and over one-third were drinking at hazardous levels.

Early adolescent cannabis exposure and positive and negative dimensions of psychosis.
Stefanis, N. C., et al.
Addiction, Vol 99(10), Oct, 2004. pp. 1333-1341.
Abstract:
Aims: To investigate the effect of exposure to cannabis early in adolescence on subclinical positive and negative symptoms of psychosis. Design: Cross-sectional survey in the context of an ongoing cohort study. Setting: Government-supported general population cohort study. Participants: A total of 3500 representative 19-year olds in Greece. Measurements: Subjects filled in the 40-item Community Assessment of Psychic Experiences, measuring subclinical positive (paranoia, hallucinations, grandiosity, first-rank symptoms) and negative psychosis dimensions and depression. Drug use was also reported on. Findings: Use of cannabis was associated positively with both positive and negative dimensions of psychosis, independent of each other, and of depression. An association between cannabis and depression disappeared after adjustment for the negative psychosis dimensions. First use of cannabis below age 16 years was associated with a much stronger effect than first use after age 15 years, independent of life-time frequency of use. The association between cannabis and psychosis was not influenced by the distress associated with the experiences, indicating that self-medication may be an unlikely explanation for the entire association between cannabis and psychosis. Conclusions: These results add credence to the hypothesis that cannabis contributes to the population level of expression of psychosis. In particular, exposure early in adolescence may increase the risk for the subclinical positive and negative dimensions of psychosis, but not for depression.

Testing the self-medication hypothesis of depression and aggression in cannabis-dependent subjects.
Arendt, Mikkel, et al.
Psychological Medicine, Vol 37(7), Jul, 2007. pp. 935-945.
Abstract:
Background: A self-medication hypothesis has been proposed to explain the association between cannabis use and psychiatric and behavioral problems. However, little is known about the reasons for use and reactions while intoxicated in cannabis users who suffer from depression or problems controlling violent behavior. Method: We assessed 119 cannabis-dependent subjects using the Schedules of Clinical Assessment in Neuropsychiatry (SCAN), parts of the Addiction Severity Index (ASI), and questionnaires on reasons for cannabis use and reactions to cannabis use while intoxicated. Participants with lifetime depression and problems controlling violent behavior were compared to subjects without such problems. Validity of the groupings was corroborated by use of a psychiatric treatment register, previous use of psychotropic medication and convictions for violence. Results: Subjects with lifetime depression used cannabis for the same reasons as others. While under the influence of cannabis, they more often experienced depression, sadness, anxiety and paranoia, and they were less likely to report happiness or euphoria. Participants reporting problems controlling violent behavior more often used cannabis to decrease aggression, decrease suspiciousness, and for relaxation; while intoxicated they more often reacted with aggression. Conclusions: Subjects with prior depression do not use cannabis as a means of self-medication. They are more likely to experience specific increases of adverse symptoms while under the influence of cannabis, and are less likely to experience specific symptom relief. There is some evidence that cannabis is used as a means of self-medication for problems controlling aggression.

Cannabis users differ from non-users on measures of personality and schizotypy.
Fridberg, Daniel J., et al.
Psychiatry Research, Vol 186(1), Mar 30, 2011. pp. 46-52.
Abstract:
Accumulating evidence indicates that cannabis use may be a risk factor for schizophrenia (SZ), and chronic cannabis users score higher than non-users on measures of schizotypal personality traits. The purpose of the present study was to investigate the relations between normal personality, schizotypy, and cannabis use. Sixty-two chronic cannabis users and 45 cannabis-naïve controls completed a measure of normal personality, the NEO-Five Factor Inventory (NEO-FFI), and two measures of schizotypy, the schizotypal personality questionnaire (SPQ) and perceptual aberration scale (PAS). Substance use was assessed using the SCID I alcohol/drug module and a locally developed drug use questionnaire. On the NEO-FFI, users scored higher than controls on openness, but lower on agreeableness and conscientiousness, and endorsed greater schizotypy on the SPQ and PAS. Higher neuroticism predicted greater schizotypy in both groups, and, higher Extraversion predicted lower negative-syndrome schizotypy among users. Finally, duration of cannabis use was positively correlated with scores on the SPQ and PAS among users, suggesting a relation between overall cannabis use chronicity and schizotypy. These data show that cannabis users differ from non-users on dimensions of normal personality and schizotypy, and provide further evidence that cannabis use is associated with increased levels of psychosis-related personality traits.

The impact of comorbid cannabis and methamphetamine use on mental health among regular ecstasy users.
Scott, Laura A., et al.
Addictive Behaviors, Vol 37(9), Sep, 2012. pp. 1058-1062.
Abstract:
Objective: Residual effects of ecstasy use induce neurotransmitter changes that make it biologically plausible that extended use of the drug may induce psychological distress. However, there has been only mixed support for this in the literature. The presence of polysubstance use is a confounding factor. The aim of this study was to investigate whether regular cannabis and/or regular methamphetamine use confers additional risk of poor mental health and high levels of psychological distress, beyond regular ecstasy use alone. Method: Three years of data from a yearly, cross-sectional, quantitative survey of Australian regular ecstasy users was examined. Participants were divided into four groups according to whether they regularly (at least monthly) used ecstasy only (n = 936), ecstasy and weekly cannabis (n = 697), ecstasy and weekly methamphetamine (n = 108) or ecstasy, weekly cannabis and weekly methamphetamine (n = 180). Self reported mental health problems and Kessler Psychological Distress Scale (K10) were examined. Results: Approximately one-fifth of participants self-reported at least one mental health problem, most commonly depression and anxiety. The addition of regular cannabis and/or methamphetamine use substantially increases the likelihood of self-reported mental health problems, particularly with regard to paranoia, over regular ecstasy use alone. Regular cannabis use remained significantly associated with self reported mental health problems even when other differences between groups were accounted for. Regular cannabis and methamphetamine use was also associated with earlier initiation to ecstasy use. Conclusions: These findings suggest that patterns of drug use can help identify at risk groups that could benefit from targeted approaches in education and interventions. Given that early initiation to substance use was more common in those with regular cannabis and methamphetamine use and given that this group had a higher likelihood of mental health problems, work around delaying onset of initiation should continue to be a priority.

Persecutory ideation and a history of cannabis use.
Freeman, Daniel.
Schizophrenia Research, Vol 148(1-3), Aug, 2013. pp. 122-125.
Abstract:
Background: Cannabis use is associated with the occurrence of psychotic experiences. However there are multiple distinct psychotic experiences, each likely to occur as quantitative traits in the general population. In this study we tested for an association of cannabis use with a dimensional assessment of persecutory ideation. Method: A total of 1714 individuals from the general population completed a dimensional measure of current persecutory ideation and reported on whether they had ever taken cannabis. Results: Of all participants, 648 (38%) reported a history of cannabis use. These individuals reported significantly higher current levels of persecutory ideation. The amount of variance in paranoia scores explained was low. Individuals with a history of cannabis use had almost twice the odds of reporting any paranoid ideation in the past month compared with individuals who had never taken cannabis. Conclusions: Using a state of the art assessment, the study adds to findings of an association of persecutory ideation with cannabis use.

Psychotic experiences are linked to cannabis use in adolescents in the community because of common underlying environmental risk factors.
Shakoor, Sania, et al.
Psychiatry Research, Vol 227(2-3), Jun 30, 2015. pp. 144-151.
Abstract:
Cannabis users are more likely to have psychotic experiences (PEs). The degree to which these associations are driven by genetic or environmental influences in adolescence is unknown. This study estimated the genetic and environmental contributions to the relationship between cannabis use and PEs. Specific PEs were measured in a community-based twin sample (4830 16-year-old pairs) using self-reports and parent-reports. Adolescents reported on ever using cannabis. Multivariate liability threshold structural equation model-fitting was conducted. Cannabis use was significantly correlated with PEs. Modest heritability (37%), common environmental influences (55%) and unique environment (8%) were found for cannabis use. For PEs, modest heritability (27–54%), unique environmental influences (E = 12–50%) and little common environmental influences (11–20%), with the exception of parent-rated Negative Symptoms (42%), were reported. Environmental influences explained all of the covariation between cannabis use and paranoia, cognitive disorganization and parent-rated negative symptoms (bivariate common environment = 69–100%, bivariate unique environment = 28–31%), whilst the relationship between cannabis use and hallucinations indicated familial influences. Cannabis use explains 2–5% of variance in positive, cognitive, and negative PEs. Cannabis use and psychotic experience co-occur due to environmental factors. Focus on specific environments may reveal why adolescent cannabis use and psychotic experiences tend to ‘travel together’.

Concurrent and sustained cumulative effects of adolescent marijuana use on subclinical psychotic symptoms.
Bechtold, Jordan, et al.
The American Journal of Psychiatry, Vol 173(8), Aug 1, 2016. pp. 781-789.
Abstract:
Objective: Adolescents who regularly use marijuana may be at heightened risk of developing subclinical and clinical psychotic symptoms. However, this association could be explained by reverse causation or other factors. To address these limitations, the current study examined whether adolescents who engage in regular marijuana use exhibit a systematic increase in subclinical psychotic symptoms that persists during periods of sustained abstinence. Method: The sample comprised 1,009 boys who were recruited in 1st and 7th grades. Self-reported frequency of marijuana use, subclinical psychotic symptoms, and several time-varying confounds (e.g., other substance use, internalizing/externalizing problems) were recorded annually from age 13 to 18. Fixed-effects (within-individual change) models examined whether adolescents exhibited an increase in their subclinical psychotic symptoms as a function of their recent and/or cumulative history of regular marijuana use and whether these effects were sustained following abstinence. Models controlled for all time-stable factors (default) and several time-varying covariates as potential confounds. Results: For each year adolescent boys engaged in regular marijuana use, their expected level of subsequent subclinical psychotic symptoms rose by 21% and their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. The effect of prior regular marijuana use on subsequent subclinical psychotic symptoms persisted even when adolescents stopped using marijuana for a year. These effects were after controlling for all time-stable and several time-varying confounds. No support was found for reverse causation. Conclusions: These results suggest that regular marijuana use may significantly increase the risk that an adolescent will experience persistent subclinical psychotic symptoms.

Factor structure of the cannabis experiences questionnaire in a first‐episode psychosis sample.
Birnbaum, Michael L., et al.
Early Intervention in Psychiatry, Oct 20, 2017.
Abstract:
Aim The Cannabis Experiences Questionnaire (CEQ) was developed to measure the subjective experiences of cannabis use both during and after intoxication. Despite the need to better understand the nature of the complex and significant relationship between cannabis use and early psychosis, this questionnaire has rarely been used in individuals with first‐episode psychosis. Methods We conducted a set of factor analyses using CEQ data from 194 first‐episode psychosis patients who used cannabis in order to uncover the underlying factor structure of the questionnaire and thus the overarching types of psychological experiences during/after using cannabis in young people with psychotic disorders. Results Our exploratory factor analysis identified 4 subscales, including: Distortions of Reality and Self‐Perception (Factor 1), Euphoria Effects (Factor 2), Slowing and A. motivational Effects (Factor 3), and Anxiety and Paranoia Effects (Factor 4). Conclusions Elucidating the underlying factor structure of the CEQ in first‐episode psychosis samples could help researchers move towards a deeper understanding of the types of experiences associated with cannabis intoxication among young adults with first‐episode psychosis and could inform the development of programs designed to reduce use, improve the course of illness, and possibly delay or prevent the onset of psychotic symptoms in those at risk.