Psychosis / Schizophrenia

Development Over Time of the Population-Attributable Risk Fraction for Cannabis Use Disorder in Schizophrenia in Denmark

July 21, 2021

Carsten Hjorthøj, PhD1,2,3Christine Merrild Posselt, MSc1Merete Nordentoft, DrMedSc1,3Author AffiliationsJAMA Psychiatry. 2021;78(9):1013-1019. doi:10.1001/jamapsychiatry.2021.1471

Abstract

Importance  Cannabis use and potency of cannabis have increased during the past 2 decades. If the association between cannabis use and schizophrenia is causal, this should be reflected in an increase in the proportion of cases of schizophrenia being attributable to cannabis, the population-attributable risk fraction (PARF).

Objective  To determine whether the PARF for cannabis use disorder in schizophrenia has increased over time.

Design, Setting, and Participants  This nationwide, register-based historical prospective cohort study included all people in Denmark born before December 31, 2000, who were alive and 16 years or older at some point from January 1, 1972, to December 31, 2016. Data analysis was performed from August 2020 to April 2021.

Exposure  Diagnosis of cannabis use disorder.

Main Outcomes and Measures  Diagnosis of schizophrenia, with estimated PARF of cannabis use disorder in schizophrenia from 1972 to 2016.

Results  A total of 7 186 834 individuals were included in the analysis, including 3 595 910 women (50.0%) and 3 590 924 men (50.0%). The adjusted hazard ratio for schizophrenia fluctuated at approximately 4 (with 95% CIs ranging from approximately 3 to 6) throughout most of the study period when people diagnosed with cannabis use disorder were compared with those without cannabis use disorder. The PARF of cannabis use disorder in schizophrenia also fluctuated, but with clear evidence of an increase from 1995 (when the PARF was relatively stable around 2.0%, with a 95% CI of approximately 0.3% to either side) until reaching some stability around 6.0% to 8.0% (with a 95% CI of approximately 0.5% to either side) since 2010.

Conclusions and Relevance  The results from these longitudinal analyses show the proportion of cases of schizophrenia associated with cannabis use disorder has increased 3- to 4-fold during the past 2 decades, which is expected given previously described increases in the use and potency of cannabis. This finding has important ramifications regarding legalization and control of use of cannabis.

Is it true that marijuana triggers transient psychotic episodes?

Dr. Christine Miller

Yes. Even with the low strength pot common in the last century, 15% of users reported psychotic
episodes:
https://www.sciencedirect.com/science/article/abs/pii/S037687169601277X?via%3Dihub
But the proof would have to await studies in the clinic, where it was found that administration of a moderate dose of pure THC would elicit transient psychotic symptoms in study subjects:
https://www.nature.com/articles/1300496.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055738/pdf/npp2010222a.pdf
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1107444
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332941/pdf/sbu098.pdf

Is there also a link to chronic psychosis (schizophrenia) in adolescent use?

Dr. Christine Miller

Yes, and not just in adolescents. For a long while, the psychiatric community was unsure of the
causal basis for the connection, because studying cause and effect is a complicated endeavor. It was
important to find out if there was a greater effect at higher dose, which would indicate causality,
and such a relationship was confirmed:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)92620-1/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC135493/pdf/1212.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877688/pdf/nihms534094.pdf
https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00117-5/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988731/
Another element of the causal connection was to determine which came first, the marijuana use or
the psychosis:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539839/pdf/bmj33000011.pdf
https://www.cambridge.org/core/services/aop-cambridgecore/content/view/D5CAA12A5F424146DABB9C6A6AB4CB56/S0007125017000526a.pdf/adolescen
t_cannabis_use_baseline_prodromal_symptoms_and_the_risk_of_psychosis.pdf

Those at the forefront of such studies were eventually convinced that the association was causal:
https://www.researchgate.net/publication/323899315_Cannabis_and_psychosis_What_do_we_kno
w_and_what_should_we_do

The consensus is that use of marijuana with a THC content over 10% increases the risk of a psychotic
disorder by 4 to 5-fold:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988731/
https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00117-5/fulltext

How does marijuana compare to other drugs that are associated with psychosis (LSD,
cocaine, amphetamine, methamphetamine, PCP)?

Dr. Christine Miller

Marijuana is more likely to lead to chronic psychosis than any other drug studied. About half of
those who experience a marijuana-induced psychotic break will eventually develop a schizophrenia
spectrum disorder:
https://www.psychiatrist.com/jcp/article/Pages/2013/v74n01/v74n0115.aspx
https://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2017.17020223?rfr_dat=cr_pub%3Dpub
med&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=ajp

Does having schizophrenia in your genetics mean that you would have manifested the
disorder anyway?

Dr. Christine Miller

No one is predestined to develop schizophrenia based on their genetics. Even if you have an
identical twin who develops schizophrenia, only about half the time will the other twin develop
schizophrenia as well. Environmental factors, like marijuana, can make the difference between
leading a normal life and not.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC335617/pdf/pnas00677-0218.pdf
For clinical studies showing that THC can cause psychotic symptoms in people with no family history,
see: https://www.nature.com/articles/1300496.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055738/pdf/npp2010222a.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332941/pdf/sbu098.pdf
In Denmark, they found that for those who experienced psychosis from marijuana, a family history
of psychosis did not determine who progressed to developing schizophrenia; very many became
schizophrenic from marijuana without having a family history:
http://archpsyc.ama-assn.org/cgi/reprint/65/11/1269

Is there an age where it is MORE risky to develop mental illness, such as 13 or 15?

Dr. Christine Miller

In the case of bipolar disorder, an early age of onset is more commonly seen in those with a family
history of the disease:
https://pubmed.ncbi.nlm.nih.gov/16449477/
and, those early onset cases have been reported to be more severe than adult onset cases:
https://pubmed.ncbi.nlm.nih.gov/19931918/
However, for schizophrenia, original findings of a worse prognosis when the diagnosis occurs as
early as thirteen years of age:
https://pubmed.ncbi.nlm.nih.gov/25792697/
have now been challenged by a much larger and more recent study, showing that early onset
schizophrenia does not carry a worse prognosis:
https://www.sciencedirect.com/science/article/abs/pii/S0920996420301559
For drug-induced mental illness, while there is some data showing use of marijuana at those young
ages is more likely to lead to chronic mental illness because the brain is still developing, this does
not mean it is safe to begin use after the teenage years. A recent study in Europe demonstrated
that frequency of use, no matter what the age when use began, was the most significant risk factor
for a psychotic break:
https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00117-5/fulltext
Irrespective of the age when a marijuana-induced psychotic break occurs, ceasing use is crucial to
improving the odds of recovery (about 50% can recover):
https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00363-6/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080669/pdf/sbp126.pdf

Association of High-Potency Cannabis Use With Mental Health and Substance Use in Adolescence

Results  Past-year cannabis use was reported by 1087 participants (580 women; mean [SD] age at onset of cannabis use, 16.7 [3.0] years). Of these, 141 participants (13.0%) reported the use of high-potency cannabis. Use of high-potency cannabis was associated with increased frequency of cannabis use (adjusted odds ratio [AOR], 4.38; 95% CI, 2.89-6.63), cannabis problems (AOR, 4.08; 95% CI, 1.41-11.81), and increased likelihood of anxiety disorder (AOR, 1.92; 95% CI, 1.11-3.32). Adjustment for frequency of cannabis use attenuated the association with psychotic experiences (AOR 1.29; 95% CI, 0.67-2.50), tobacco dependence (AOR, 1.42; 95% CI, 0.89-2.27), and other illicit drug use (AOR, 1.29; 95% CI, 0.77-2.17). There was no evidence of association between the use of high-potency cannabis and alcohol use disorder or depression.

Conclusions and Relevance  To our knowledge, this study provides the first general population evidence suggesting that the use of high-potency cannabis is associated with mental health and addiction. Limiting the availability of high-potency cannabis may be associated with a reduction in the number of individuals who develop cannabis use disorders, the prevention of cannabis use from escalating to a regular behavior, and a reduction in the risk of mental health disorders.

Cannabis use in adolescence and risk of psychosis: Are there factors that moderate this relationship? A systematic review and meta-analysis\

Sarah Kanana Kiburi 1 2Keneilwe Molebatsi 3 4Vuyokazi Ntlantsana 4Michael T Lynskey 5Affiliations expand

Previous research has reported increased risk for psychosis among individuals who use cannabis during adolescence. We conducted a systematic review and meta-analysis to investigate the interaction between adolescent cannabis use and other factors in moderating risk for psychosis later in life. Method: We searched four electronic databases in June 2020 for articles that assessed adolescent cannabis use, had psychosis as an outcome and analyzed for the association between adolescent cannabis use and psychosis. Analysis was done using random-effects meta-analysis and narrative synthesis. Results: A total of 63 studies were included in the narrative review and 18 studies were included in the meta-analysis. Adolescent cannabis use was found to increase risk for psychosis (RR = 1.71 (95%CI, 1.47-2.00, p < 0.00001) and predict earlier onset of psychosis. The following factors moderate the relationship between cannabis use and the risk of psychosis: age of onset of cannabis use, frequent cannabis use, exposure to childhood trauma, concurrent use of other substances and genetic factors. 

Conclusion: Adolescent cannabis use is associated with an increased risk for psychosis later in life. In addition, there are factors that moderate this relationship; therefore there is a need for research to assess the interaction between these factors, adolescent cannabis use and psychosis risk.

The Bradford Hill Analysis of Causation Applied to Cannabis Use and
the Development of Chronic Psychotic Disorders
Christine L. Miller, Ph.D., Catherine Antley, MD and Dean Whitlock (editor)
with a review and contributions from Carsten Hjorthoj, Ph.D., Associate Professor,
Copenhagen Research Center for Mental Health, University of Copenhagen;

Cannabis use in children and adolescents with first episode psychosis: influence on psychopathology and short-term outcome (CAFEPS study)

https://pubmed.ncbi.nlm.nih.gov/19427172/#:~:text=Schizophr%20Res,2009%20May%207.

Immaculada Baeza 1Montserrat GraellDolores MorenoJosefina Castro-FornielesMara ParelladaAna González-PintoBeatriz PayáCésar SoutulloElena de la SernaCelso ArangoAffiliations expand

Abstract

Objective: To know the prevalence of substance use and its relationship with psychopathology at onset and after six months in children and adolescents with first episode psychosis (FEP).

Method: 110 FEP patients, aged 9-17, were assessed for substance use, and with the Positive and Negative Syndrome Scale (PANSS) and other psychopathological and general functioning scales at baseline and after a six-month follow-up.

Results: Patients’ substance use at baseline was: tobacco (30.9%), cannabis (29.1%), alcohol (21.8%), cocaine (8.2%), amphetamines (2.7%), LSD (1.8%) and opiates (0.90%). Six months later, there was a decrease in patients’ use of cannabis (p=0.004) and other drugs, except tobacco. Patients were divided, according to their baseline cannabis use, into 32 cannabis users (CU) and 78 non-cannabis users (NCU). CU were older (p=0.002) and had higher PANSS positive scores (p=0.002) and lower PANSS negative (p<0.001), PANSS general (p=0.002) and PANSS total (p=0.007) scores than NCU. At six months, CU had significantly lower PANSS positive (p=0.010), negative (p=0.0001), general (p=0.002) and total (p=0.002) scores than NCU. When we divided CU at six months into previous CU (n=16) and current CU (n=15), previous CU had the best outcome, NCU the worst and current CU had an intermediate profile.

Conclusions: Cannabis use may be related to higher positive symptom scores for FEP patients, with greater improvement after six months for those who cease using cannabis.