The risk of Cannabis use on mental health is of particular concern due to its growing availability and widely accepted safety profile following recent and pending relaxation in laws governing its possession and distribution in many countries. In England, it was recently downgraded from class B to C, only to be upgraded to class B following media investigations into the impact on mental health of the more potent strains readily available. Cannabis use has been strongly linked to the development of psychosis. Particularly hybrid strains of Cannabis with unnaturally high THC content and a high THC to CBD ratio (Englund A, et al. 2013).

In 1969 a large study on 50,000 Swedish army draftees concluded that there was a greater risk of developing psychosis with cannabis use, which increased in a dose dependent rate and with earlier age of initiation. These findings were further enforced with successive follow up studies of the same individuals years later (Zammit et al., 2002).  Parallel studies surveying large numbers of test subjects found the odds ratio of developing psychosis as being between 1.5 and 3.2. This was further explored by Arseneault et al (2002) who confirmed by screening 26-year-old test subjects, that earlier use increased the odds ratio by almost 3-fold in a comparison of initiation age 15 against age 18. This implies that use of Cannabis has a far greater long-term impact on younger people whose brains are in a more rapid phase of growth and that the psychosis vulnerability was amplified when Cannabis use began during this critical development phase.

Cannabinoids act in the brain on the CB1 pre-synaptic receptor, which plays a part in regulating glutamate and GABA receptor signalling, notably the NMDA glutamate receptor which if dysfunctional can augment the risk of psychosis (Kruk-Slomka et al., 2016). The CB1 receptor is crucial in regulating calcium ion influx at the NMDA receptor, without which the NMDA receptors would become hyperactive and cause cytotoxicity. The NMDA receptors provide a feedback mechanism to the endogenous cannabinoid pathway in order to regulate their calcium level and keep it within a safe operating level.  This feedback system is delicately tuned so the endocannabinoid system is in harmonic response with NMDA communication. Introducing exogenous cannabinoids can destabilize this system. THC is a partial agonist to the CB1 receptor and has been shown to reduce long term potentiation of hypocampus glutamatergic signalling and reduce the NMDA cellular expression (Sánchez-Blázquez et al, 2014). Synthetic Cannabinoids are known to be particularly agonistic at the CB1 receptor, with some having a much higher binding affinity than THC which could be a reason for the higher prevalence of psychosis with use of particular varieties of synthetic Cannabinoids such as K2 than with Cannabis of plant origin (Fantegrossi et al., 2014).

CBD is a proven antipsychotic which counterbalances THC to some extent in natural strains of cannabis. However, hybridization to produce ever more potent strains of cannabis has been blamed for an increasing incidence in cannabis psychosis. A study conducted by Di Forti (2015) showed that regular hash users had an odds ratio for a first-time psychotic episode not statistically different to a control group who had never used Cannabis. Whilst skunk use at any frequency increased the odds ratio on average 3x greater than the control group and 5.4x greater than control for those who used Skunk daily.

Cannabis has been shown to induce temporary psychosis in some users, long-term psychosis in others, whilst exacerbating it in those already possessing a psychotic disorder. Although there is no conclusive evidence showing that Cannabis can precipitate a psychotic disorder in those who have no inherent predisposition. Additionally, skeptics of cannabis psychosis theory opine that some of the genes playing a role in schizophrenia may also elicit a greater tendency for cannabis use. This may be a valid explanation considering that in some countries, cannabis use has increased but there has not been a correlative increase in psychosis predicted by the theory (Gage et al, 2016). Furthermore, Cannabis users are more likely to use other drugs, many of which augment the risk of psychosis and thus skew the results in favour of the Cannabis psychosis theory.

Research clearly indicates a high probability that Cannabis use can cause emergence of psychosis which may be transitory in some or long term in others. Whether this is a direct result of its neurological effects is inconclusive as other factors such as latency of psychosis and the individual’s greater desire to experiment or self-medicate with Cannabis may be due to underlying biological -factors and give false positive data in support of the Cannabis-psychosis theory.

 

References:-

Gage SH, Hickman M, Zammit S. (2016). Association between cannabis and psychosis: epidemiologic evidence. Biological Psychiatry 2016; 79: 549–56

Englund A, Morrison PD, Nottage J, et al. (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 2013.

Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. (2002). Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: Historical Cohort Study. Biomedical Journal 2002 Nov 23;

Kruk-Slomka, M., Budzynska, B., Slomka, T., Banaszkiewicz, I., & Biala, G. (2016). The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801. Neurotoxicity research, 30(4), 658–676. doi:10.1007/s12640-016-9662-0

Sánchez-Blázquez P, Rodríguez-Muñoz M and Garzón J (2014). The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Frontiers in Pharmacology 4:169.

Marta Di Forti, Arianna Marconi et al., (2015). Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. The Lancet Psychiatry, Volume 2, Issue 3, P233-238, March 01, 2015

Fantegrossi W.E., Moran J.H., Radominska-Pandya A, Prather P.L. (2014). Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity? Life Sciences. 2014 Feb 27;97(1):45-54. doi: 10.1016/j.lfs.2013.09.017. Sep 29.