By Kevin She
22 Mar 2016
Even before the 1937 film Reefer Madness concerns over the potential harm of Cannabis and cannabinoid use have been raised as early as 1903 by John Warnock, then as the medical director of the Egyptian Hospital for the Insane, in an article in the British Journal of Psychiatry entitled Insanity From Hasheesh (Warnock 1903). Since then there has been a huge body of evidence suggesting an association of many harms such as impaired cognition (decreased IQ) and increased risk of psychosis/schizophrenia with heavy Cannabis use, and especially so in heavy users who started at younger ages. What is the current evidence for the risk of using Cannabis and cannabinoids? With increasing acceptance of Cannabis as a medicine for an increasing number of conditions, are patients trading one illness for another harm?
Figure 1: A Rake’s Progress: Bedlam
Cannabis – marijuana – is by far, barring alcohol, the most widely cultivated, trafficked, and used drug in the world with a lifetime use prevalence of about 40% in Canada (CADUMS 2008-2011) and about 50% in the United States (ICPSR34481-v1). With increasing legalization for both medical and recreational use, evaluation of the mental health risks of cannabinoids is increasingly salient.
While there have been many studies showing an association of Cannabis use with decreased intelligence (Block & Ghoneim 1993, among many others), reduced memory (Solowij &al., 2002, among many others), and lower verbal ability (Fontes &al., 2011, among many others), these studies are almost always longitudinal studies. A longitudinal study is a research method that relies on retroactively observed data of a population; for example, they take a cohort of children (presumably before they initiated use), administer an IQ test, wait several years, and administer another IQ test along with a survey of whether they used Cannabis and how much. Afterwards, they compare the IQ scores of users versus non-users to see if there is an association of decreased IQ with Cannabis use. A major limitation of these longitudinal studies is that while they can demonstrate whether there is an association or not, this method is not able to demonstrate that there is causation between use and cognitive decline. Other limitations to high quality research is that in the United States Cannabis and its products remain schedule I substances and requires a difficult to acquire Drug Enforcement Agency Schedule I license to possess (Cannabis and its products are schedule II substance in Canada and also requires similarly difficult to acquire possession licenses) and that research institutions and funding agencies have in the past been often reluctant to grant approval for research. As a result, research has historically been limited to retrospective cohort studies, individual case report, and observational studies which are often inconclusive and burdened by methodological inconsistency.
While most studies in the past have focused on the hypothesis that Cannabis use is a contributing cause of mental health risks, more current studies are increasingly acknowledging the alternate hypothesis that there may be common contributing risks for the combination of mental disorders and Cannabis use – or even that mental health disorders increases the risk of Cannabis use.
Since a study where a large number of children are randomly divided into different groups and forcibly made to ingest different amounts of different mixtures of cannabinoids over many years could never receive ethical approval, a recent highly powered (many participants to counteract the heterogeneity of human subjects, in this case 1,241 and 2,527 individuals in two separate cohorts) study investigated Cannabis use in monozygotic (identical) and dizygotic (fraternal) twins (and some triplets) where one twin reported using marijuana and the other twin did not (Jackson &al., 2016). The advantage to this study is that there is better control over genetics (twins) and environment (same household) when comparing users and non-users.
Indeed, declines in verbal ability (vocabulary) and general knowledge (information) were associated with Cannabis use – when considered in aggregate (all users versus all non-users). However, when comparing a twin who used to their twin who didn’t, there were no differences in changes in verbal ability or general knowledge between the twins suggesting that the individuals would have experienced declines (or did not keep up with expected gains with their peers) whether they used Cannabis or not. Another interesting observation was that individuals who would go on to use Cannabis (and their twin) already had lower test scores prior to initiating use.
The limitation of the study is that it was not able to demonstrate any mechanisms for the association of lower initial test scores with future Cannabis use; the authors propose that familial-cultural deficits (less parental supervision, poor parent-child relationship, less emphasis on scholarship and civic responsibility) may account for lower test scores and Cannabis use. Similar findings have been discovered for tobacco (Fried &al., 2006) and alcohol (Latvala &al., 2011) use in youth and the associations may be a result of familial-cultural deficits rather than that use itself directly affects cognition.
Schizophrenia is a serious psychiatric disorder that is highly complex and poorly understood. The definition and diagnosis of schizophrenia has been controversial since it was first introduced in 1911 (Hallmayer 2004, Nemeroff &al., 2013). Furthermore, the diagnostic criteria are based solely on clinical presentation as no biomarkers (physical measurable indicator of the presence of severity of a disease state) have been discovered to provide a definitive diagnosis. As such, diagnosis and treatment is controversial within the psychiatric community (Owen &al., 2016) especially after the release of the DSM-V (Diagnostic and Statistical Manual of Mental Disorders, 5th edition). Core features of schizophrenia are delusions, hallucinations, impaired motivation, reductions in spontaneous speech, and social withdrawal. Additional features may include cognitive impairment and episodes of elevated or depressed mood.
Patients diagnosed with schizophrenia are more likely to report current and/or previous use of Cannabis and the association of Cannabis use and schizophrenia has been widely observed in many parts of the world including Italy (Allegri &al., 2013), the USA (Bahorik &al., 2014), Sweden (Manrique-Garcia &al., 2012), France (Lejoyeux &al., 2014), and South Africa (Pruk &al., 2013).
However, a large number of other factors have also been strongly linked to the development of schizophrenia including family history of schizophrenia (suggesting a genetic component), exposure to environmental toxins or infections in utero (as a fetus), older age of the father, birth month (possibly related to vitamin D deficiency) (DSM-V), or possibly even growing up in the presence of housecats (Fuller &al., 2015). Tobacco use in patients diagnosed with schizophrenia occurs at vastly higher frequencies compared to other people in their geographic area (Kelly & McCreadie 2000). As such, Cannabis use is one of many factors that are associated with the diagnosis of schizophrenia including childhood maltreatment, school adjustment, and social adjustment (Broussard &al., 2013).
Also, many studies of the relationship between Cannabis use and schizophrenia rely on self-reported surveys of “psychotic experiences” (PE) to show that early and heavy users of Cannabis have elevated numbers of PE compared to non-users. Typical questions to assess PEs include whether someone has experienced 1) Paranoia, 2) Hallucinations (the perception of something that isn’t there), 3) Cognitive disorganization (inability to concentrate and maintain a train of thought), 4) Grandiosity (unrealistic sense of superiority), and 5) Anhedonia (the inability to feel pleasure) (Shakoor &al., 2015).
Interestingly, a commonly used survey (SPEQ) given to a large cohort of 16 year olds returned some interesting results (Ronald &al., 2013). For the hallucination question, “How often do you hear voices commenting on what you’re thinking or doing?” the responses were:
____________________________________Reverse Cumulative %
For the paranoia question, “How often have you thought I need to be on my guard against others?” the responses were:
____________________________________Reverse Cumulative %
The Shakoor &al., 2015 study includes many of the same senior authors in the Ronald &al., 2013 study and uses the same SPEQ survey. The results?
The percentage of Cannabis users reporting hallucinations is similar to those who report hallucinations at least once a month among the general population of 16 year olds and reports of paranoia are similar to those who report paranoia at least once a week. The differences between non-Cannabis users and Cannabis users are statistically significant but the effect size is not terribly large.
Psychiatric disorders in general are genetically complex; different polymorphisms (usually small differences such as a small mutation in a gene) of the same gene can produce very different outcomes and polymorphisms in different genes can produce quite similar effects. There are many candidate genes that may cause schizophrenia, which itself may be many different conditions that are grouped under one catch-all classification (Owen &al., 2016), much like autism-spectrum disorders. Indeed, schizophrenia may involve a complex constellation of many different genes all subtly affecting brain development and brain function.
One gene that has attracted attention is AKT1 (COMT is another candidate that has gained attention but strong conclusions are difficult to draw (Williams &al., 2007)). AKT1 is an enzyme that is central to many cell functions including metabolism, proliferation, cell survival, growth, angiogenesis (the development of blood vessels and capillaries), and plays a subtle role in brain development and continued brain function. In an early study, the amount of AKT1 proteins was found to be decreased in schizophrenic individuals (Emamian &al., 2004).
An early study investigating the mechanism between the relationship of AKT1 and schizophrenia stratified individuals diagnosed with schizophrenia that used or did not use Cannabis prior to being diagnosed and administered a sustained memory test. The individuals were further subdivided depending on whether they had the T/T, T/C, or C/C variant of AKT1. The performance of the T/T and T/C groups were similar regardless of former use of Cannabis whereas the C/C group had decreased accuracy and reaction time if they had ever used Cannabis even if they were not a current user.
More recently, the C/C specific variant of AKT1 was found to increase the effects of Cannabis (which the authors call “psychotic response to cannabis”) and suggested that this may be a mechanism where Cannabis may contribute to schizophrenia (Morgan &al., 2016).
Taken as a whole, however, Cannabis in itself is likely not a direct cause of schizophrenia in the general population. Rather, both early use and heavy use in individuals may be a symptom of vulnerability to a variety of other problem behaviors such as early or heavy use of cigarettes, alcohol, other illicit drugs, and poor school performance; the same vulnerabilities that might also result in increased risk for schizophrenia and other mental disorders (Ksir & Hart 2016).
While the use of Cannabis may not directly cause cognitive defects or schizophrenia, recreational Cannabis use, like other euphorics and alcohol, should be discouraged in youth as they are still developing coping mechanisms for life’s situations and narcotic use may impair the development of health life skills.
‘It has been argued that even if we are uncertain that cannabis actually causes psychosis, it is better to err on the side of caution and warn cannabis users, psychiatric patients, and the general public about this potential danger of cannabis use. However, those adolescents most at risk for beginning cannabis use are already suspicious about official warning messages when it is perfectly clear that cannabis use is not approved by the general society. If we wish scientists to be taken seriously when we do discover real and substantial dangers, then we believe it would be better to avoid behaving like “the boy who cried wolf.”’
(Ksir & Hart 2016)
Long term cognitive effects of Cannabis use in adults have been less well studied. However, with the increasing legalization of medicinal and recreational use of Cannabis, perhaps there will be a cohort of individuals who initiated Cannabis use only in adulthood who can be used to investigate whether there are any long term negative cognitive effects of Cannabis use in adults.
Allegri, F. Belvederi-Murri, M., Paparelli, A., Marcacci, T., Braca, M., Menchetti, M., Michetti, R., Berardi, D., & Tarricone, I. 2013 Current cannabis use and age of psychosis onset: a gender-mediated relationship? Results from an 8-year FEP incidence study in Bologna. Psych. Res. 210(1): 368-70
Bahorik, AL. Newhill, CE., & Eack, SM. 2013 Neurocognitive functioning of individuals with schizophrenia: using and not usig drugs. Schizophr. Bull. 40(4): 856-67
Block, RI., & Ghoneim, MM. 1993 Effects of chronic marijuana use on human cognition. Psychopharm. (Berl) 110(1-2): 219-28
Broussard, B., Kelley, ME., Wan, CR., Cristofaro, S., Crisofio, A., Haggard, PJ., Myers, NL., Reed, T., & Compton, MT. 2013 Demongraphic, social environment, and substance-related predictors of duration of untreat psychosis (DUP). Schizophr. Res. 148(1-3): 93-8
DSM-V: American Psychiatric Association, 2013 Diagnostic and statistical manual of mental disorders: DSM-5, 5th ed. Washington, D.C. p947
Emamian, ES., Hall, D., Birnbaum, MJ., Karayiorgou, M.,, & Gogos JA. 2004 Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat. Genet. 36: 131-7
Fontes, MA., Bolla, KI., Cunha, Jannuzzi Cunha, P., Previato Almeida, P., Jungerman, F., Laranjeira, RR., Bressan, RA., Lacerda, ALT. 2011 Cannabis use before age 15 and subsequent executive functioning. Br. J. Pysch. 198(6): 442-7
Fried, PA., Watkinson, B., & Gray, R. 2006 Neurocognitive consequences of cigarette smoking in young adults- a comparison with pre-drug performance. Neurotox. Teratol. 28(4): 517-525
Fuller, TE., Simmons, W., & Yolken, RH. 2015 Is childhood cat ownership a risk factor for schizophrenia later in life? Schizophr. Res. 16(1): 1-2
Hallmayer, J. 2004 Getting our AKT together in schizophrenia? Nat. Genetics. 36: 115-6
Jackson, NJ., Isen, JD., Khoddam, R., Irons, D., Tuvblad, C., Iacono, WG., McGue, M., Raine, A., & Baker, LA. 2016 Impact of adolescent marijuana use on intelligence: results from two longitudinal twin studies. PNAS 113(5): E500-508
Kelly, C. & McCreadie, R. 2000 Cigarette smoking and schizophrenia. Adv. Psych. Treat. 6(5): 327-31
Ksir, C. & Hart, CL. 2016 Cannabis and psychosis: a critical overview of the relationship. Curr. Pyshciatry Rep. 18(2): 12
Latvala, A., Tuulio-Henriksson, A., Dick, DM., Vuoksimaa, E., Viken, RJ., Suvisaari, J., Kaprio, J., & Rose, RJ. 2011 Genetic origins of the association between verbal ability and alcohol dependence symptoms in young adulthood. Psychol. Med. 41(3): 641-51
Lejoyeux, M., Basquin, A., Koch, M., Embouazza, H., Chalvin, F., & Ilongo, M.2014 Cannabis use and dependence among French schizophrenic inpatients. Front. Psych. doi: 10.3389/fpsyt.2014.00082
Manrique-Garcia, E., Zammit, S., Dalman,, C., Hemmingsson, T., Andreasson, S., & Allebeck, P. 2012 Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol. med. 4296): 1321-8
Morgan, CJA., Freeman, TP., Powell, J., & Curran, HV. 2016 AKT1 genotype moderates the acute psychomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Trans. Psych. doi: 10.1038/tp.2015.219
Nemeroff, CB., Weinberger, D., Rutter, M., MacMillan, HL., Bryant, RA., Wessely, S., Stein, DJ., Pariante, CM., Seemuller, F., Berk, M., Malhi, GS., Preisig, M., Brune, M., & Lysaker, P. 2013 DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions. BMC Medicine 11: 202
Owen, MJ., Sawa, A., & Mortensen, PB. 2016 Schizophrenia. Lancet doi: 10.1016/S0140-6736(15)01121-6
Paruk, S., Burns, JK., & Caplan, R. 2013 Cannabis use and family history in adolescent first episode psychosis in Durban, South Africa. J. Child Adolesc. Ment. Health. 25(1): 61-8
Ronald, A., Sieradzka, D., Cardno, AG., Haworth, CMA., McGuire, P., & Freeman, D. 2013 Characterization of psychotic experiences in adolescence using the specific psychotic experiences questionnaire: findings from a study of 5000 16-year-old twins. Schiz. Bull. 40(4): 868-77
Shakoor, S., Zavos, HMS., McGuire, P., Cardno, AG., Freeman, D., & Ronald, A. 2015 Psychotic experiences are linked to cannabis use in adolescents in the community because of common underlying environmental risk factors. Psych. Res. 227(2-3): 144-51
Solowij, N., Stephens, RS., Roffman, RA., Babor, T., Kadden, R., Miller, M., Christiansen, K., McRee, B., Vendetti, J.
Warnock, J. 1903 Insanity from hasheesh. Br. J. Psych. 49(204): 96-110
Williams, HJ., Owen, MJ., & O’Donovan, MC. 2007 Is COMT a susceptibility gene for schizophrenia? Schiz. Bull. 33(3): 635-41