5 + 10 + 15

topics in child, adolescent, and young adult psychiatry…

Cannabis & Psychosis: a brief review

Craigan Usher, MD

5 Papers

1. Silva TB, Balbino CQ, Weiber AF. The relationship between cannabidiol and psychosis: a review. Ann Clin Psychiatry. 2015;27(2):134-41.

2. Rigucci S, Marques TR, Di Forti M, et al. Effect of high-potency cannabis on corpus callosum microstructure. Psychol Med. 2015;27:1-14. [Epub ahead of print]

3. Smeerdijk M, Keet R, van Raaij B, et al. Motivational interviewing and interaction skills training for parents of young adults with recent-onset schizophrenia and co-occurring cannabis use: 15-month follow-up. Psychol Med. 2015;45(13):2839-48.

4. Di Forti M, Iyegbi C, Sallis H, et al. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol Psychiatry. 2012; 15;72(10):811-6.

5. Radhakrishnan R, Wilkinson ST, D’Souza DC. Gone to Pot - A Review of the Association between Cannabis and Psychosis. Front Psychiatry. 2014 22;5:54.

10 Learning Points

  1. Cannabis is a plant which contains over 600 chemical components. Research and now consumer labeling is most focused on two major components: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).
  1. THC, particularly at high doses, is believed to be responsible for sparking feelings of anxiety, memory difficulties/time lapse, and even psychotic symptoms. CBD, meanwhile, may inhibit some of the THC-induced anxiety and psychotic-like symptoms. Some have speculated that CBD may even provide a treatment for anxiety and psychosis.
  1. CBD may exert some antipsychotic or anti-anxiety properties when consumed with THC as it inhibits degradation of anandamide, an essential amino acid neurotransmitter which blocks THC from interacting with cannaboid receptors (CB-Rs).
  1. A one month study comparing cannabidiol treatment to treatment with the antipsychotic, Amulsipride showed that while cannabidiol was better tolerated in terms of side-effects, there was no difference on the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) with either treatment. There was no placebo treatment in this study.
  1. The two major subspecies of cannabis are cannabis sativa—which tends to have a higher THC:CBD ratio and cannabis indica—which tends to have a lower THC:CBD ratio. Cannabis that is bred to be very high in THC content is often referred to as Sinsemella, or “skunk.”
  1. One recent study showed that daily smoking “skunk” or high dose THC, was associated with alterations in the microstructure of the corpus collosum (CC), these white matter changes were most significant in the posterior part of the CC including the splenium and the poster mid-body. It is speculated that the interaction of THC with Cannabinoid-1 (CB1) receptors in oligodendrocytes precursor cells may cause them to undergo apoptosis during white matter development. Recall that the corpus collosum’s primary function is to integrate inter-hemispheric activities (motor, sensory, and cognitive performance coordination between left and right).
  1. Anecdotal/clinical evidence suggests that cannabis use can catalyze long-term psychosis. A moving depiction of how cannabis may be a catalyst toward long-term psychotic illness is found in Elyn Saks’ memoir The Center Cannot Hold: My Journey Through Madness. Research suggests that brief psychotic episodes precipitated by cannabis intoxication place individuals at high risk for long-term psychotic illness and there is evidence that genetic risk may play a role in this—either that one would be at genetic risk for a certain behavior/craving (continuing to smoke which pushes one towards psychosis), that one has a predisposition (at the level of the gene) toward developing psychosis in the presence of continued use, or both.
  1. Researchers currently believe that there is a gene x gene x environment x develop timing* relationship to cannabis catalyzing psychosis. While it is not entirely clear which genes contribute to susceptibility, the gene which codes for Catechol-O-methyltransferase (COMT) on chromosome 22q11 and the AKT1 gene, which codes for a protein kinase that is important in dopamine receptor signaling in the striatum. *See the attached Blakemore SJ Teenage kicks: cannabis and the adolescent brain. Lancet 2013 16;381(9870):888-9
  1. In 2015, cannabinoid neuropharmacologist Matthew Hill compared some of the information on the connection between psychosis and cannabis to the 1936 alarmist film, Reefer Madness. He acknowledged that there may be individuals who have increased susceptibility to psychosis when using the drug, but cautions that if it was such a powerful instigating factor we should see rates of schizophrenia climb as the adolescent population increasingly has access to/uses marijuana. See Matthew Hill’s perspective piece in the September 24, 2015 issue of Nature and Large and Di Forti’s response.
  1. Until recently there were no empirically validated psychological/behavioral interventions for helping individuals with first-episode psychosis (FEP) reduce or achieve abstinence from marijuana use. However, a recent study of family motivational interviewing (FMI) versus general family support showed promise.

15 Questions

1. What are the two main subspecies of cannabis?1

  1. Cannabis sativa which tends to have higher tetrahydrocannabinol (THC) content and Cannabis indica which tends to have higher cannabidiol (CBD) content.
  2. Cannabinol and Cannabidiol.
  3. Delta-8-tetrahydrocannabinol and Tetrahydrocannabinol.
  4. Sinsemella and Spice

2. What is sinsemella?1

  1. The main psychoactive component of Cannabis sativa.
  2. The subspecies of marijuana which contains a higher concentration of cannabidiol (CBD).
  3. A strain of marijuana unlikely to produce a “high” with potential anti-psychotic and anxiolytic properties.
  4. Also known as “skunk,” this refers to a variety of marijuana that has been specially grown (with only the female plant blossoming) in order to produce a high concentration of psychoactive compounds

3. Where is the highest concentration of cannabinoid 1 receptors (CB1-R)?1

  1. In the fusiform gyrus.
  2. In the immune system,spleen, and the gastrointestinal system and, to some extent, in the brain and peripheral nervous system.
  3. The hypothalamus and pituitary gland.
  4. The substantia nigra, the basal ganglia, limbic system, hippocampus, and cerebellum

4. According to the research to date, what is one problem with cannabidiol (CBD) as it relates to being a potential treatment of the symptoms of psychosis and of cannabis use?

  1. It may inhibit degradation of anandamide—an essential fatty acid neurotransmitter.
  2. It may increase levels of delta-9-tetrahydrocannabinol (THC) in the brain and prolong the effects of THC.
  3. Compared with amisulpride, treatment with CBD was associated with significantly fewer extrapyramidal symptoms, less weight gain, and lower prolactin increase.
  4. It may promote wakefulness and memory—particularly at higher doses (CBD 600mg).

5. Using diffusion tensor imaging (DTI), researchers showed that frequent use of high potency cannabis may damage which brain structure?2

  1. The corpus collosum--the largest white matter structure in the brain.
  2. The cerebellum.
  3. The basal ganglia.
  4. The spinal cord.

6. What is the high concentration of delta-9-tetrahydrocannabinol (THC) that “skunk” might contain?2

  1. 48-52
  2. 16-22%
  3. 10-14%
  4. 8-12%

7. As the psychiatric practitioner/therapist for a small multidisciplinary team aimed at supporting young people with first-episode psychosis, you are interested in an intervention which would help your patient population reduce or halt use of cannabis. Which of best characterizes your response?3

  1. You find yourself encouraged by the large number of studies showing that treatment with antipsychotics, particularly Risperidone, is effective at helping patients with FEP reduce use of cannabis.
  2. You find yourself encouraged by the large number of studies showing psychotherapeutic interventions are effective at helping patients with FEP reduce use of cannabis.
  3. You find yourself encouraged by one long-term study comparing amulsipride to CBD treatment, showing this was effective in reducing use of “skunk.”
  4. You note that the literature to date is underwhelming, but that one study of Family Motivational Interviewing (FMI) showed promise in reducing the quantity and frequency of cannabis use and the craving for this in individuals with FEP.

8. Which of the following statements best characterizes the evidence for the anxiolytic effects of cannabidiol (CBD)?5

  1. The doses and administration routes of CBD in controlled studied is very similar to what can be achieved by “smoking a joint.”
  2. CBD seems to exert it’s clinical effects only in the presence of a stimulus—something that is anxiety-provoking or painful, mitigating the physiological response to these.
  3. There are several studies showing that it is useful in addressing symptoms of anxiety in individuals with schizophrenia spectrum disorders.
  4. It only works in the presence of high dose THC.

9. Delta-9-tetrahydrocannabinol (THC) is thought to exert it’s pro-psychotic effects through which of the following mechanisms?4

a.By direct dopamine receptor-2 (D2) agonism.

b.By inhibiting the feedback loop between the nucleus accumbensand the ventral tegmental area—thereby increasing dopamine release in the striatum.

c.Through increased inflammation.

d.By inducing apoptosis in the ventral tegmentum.

10. AKT1 is a gene that codes for a protein kinase that forms an integral part of the dopamine receptor signaling cascade in the striatum. Studies of those who are daily users of cannabis show that individuals with the cannabis risk genetic variant (C/C) of this gene versus those who are homozygous for the non-risk (T/T) variant are:4

a.Seven times as likely to develop psychosis.

b.Twice as likely to develop psychosis.

c.Just as likely to develop psychosis.

d.Seven times less likely to develop psychosis.

11. Information on the connection between the catechol-O-methyltransferase (COMT) and susceptibility to developing psychosis with cannabis use presently suggests: 4

  1. An unequivocal causal relationship between COMT gene variants and risk for developing psychosis with cannabis intoxication.
  2. Having the COMTVal108Met allelic variation is guarantee of having psychosis when smoking marijuana between the ages of 16 and 18.
  3. There is controversy about COMT allelic variants and risk for developing psychosis in the context of cannabis use, but it continues to be studied as an explanatory model for a gene (COMT) x gene (other possible susceptibility genes) x environment (cannabis) x development (susceptibility eras) interaction leading to psychotic illness.
  4. Individuals with schizophrenia should receive testing for COMT allelic variations as there is predictive value/clinical therapeutic benefit to this.

12. What is the term for synthetic cannabinoids?5

  1. Spice/K2.
  2. Skunk.
  3. Molly
  4. Bath salts

13. Regarding familial/genetic risk and cannabis-induced psychotic disorders, which of the following statements is most accurate.5

  1. According to the largest study, individuals with a family history of psychosis are no more likely to develop psychosis with cannabis use than those who do not have a family history of psychotic disorders.
  2. According to the largest study, individuals with a family history of psychosis are 2.5x’s more likely to develop psychosis with cannabis use than those who do not have a family history of psychotic disorders.
  3. Studies have been very small and show no association between family history of psychosis and risk for developing psychosis with cannabis use.
  4. This issue has not been studied.

14. According to a 2013 Finnish study of over 18,000 inpatients who were admitted to the hospital due to substance-induced psychosis, intoxication with which of the following substances was associated with the highest the 8-year cumulative risk of conversion to schizophrenia (46%)?5

  1. Alcohol.
  2. Amphetamine
  3. Cannabis
  4. Caffeine

15. What is an argument against the notion that cannabis can cause schizophrenia in individuals who, marijuana-naïve, would not go onto develop schizophrenia?*

  1. While rates of marijuana use have gone up in many adolescent populations, the rates of schizophrenia have remained the same.
  2. Daily smoking high THC content does not seem to be associated with white matter changes.
  3. Studies have shown that rates of progression to schizophrenia after hospitalization for cannabis-induced psychosis are relatively low.
  4. Cannabis and its most active most responsible for developing a “high” have not been shown to be active in brain regions that are associated with psychotic symptoms.

Answer key:

1-a / 2-d / 3-d / 3-b / 4-b / 5-a / 6-b / 7-d / 8-b / 9-b / 10-a / 11-c / 12-a / 13-b / 14-c / 15-a