Cannabis and schizophrenia: risk factor or therapeutic alternative?

By Luis F. Callado

Doctor in Medicine and Surgery. Tenured Lecturer in Pharmacology at the University of the Basque Country. Head of the master's degree course in "Pharmacology. Development, Assessment and Rational Use of Drugs". Conducts research in the field of neuropsychopharmacology. Has worked as a researcher at Oxford University and the Royal London Hospital. He has written more than 100 articles in international SCI-indexed journals, given over two hundred papers at conferences and authored several book chapters. He is also a collaborating researcher with the Networked Biomedical Research Centre (CIBER) in Mental Health.

Schizophrenia is a chronic mental disease affecting approximately 1% of the population. Onset is generally in adolescence, and its incapacitating potential persists and increases throughout the patient's lifetime. As a result, the life expectancy of schizophrenia patients is around ten years shorter than that of the general population. Because of the associated deficits and the chronic nature of the condition, schizophrenia is the fifth most costly disease for society. This high social cost is mainly due to its early onset, frequency of hospitalization, need for psychosocial support and loss of productivity.

Three groups of symptoms may be identified in schizophrenia: positive psychotic symptoms (hallucinations, delirium, confused thinking), negative symptoms (anhedonia, alogia, social withdrawal or unsociability), and cognitive symptoms (difficulty in attention, memory and executive functions). The course of schizophrenia is characterised by alternations of psychotic relapses or exacerbations and periods of partial remission where negative and cognitive symptoms predominate.

The aetiology of schizophrenia is multifactorial and there is evidence to suggest that both genetic and environmental factors may contribute to its appearance. Among these environmental factors, a number of epidemiological studies have suggested that cannabis use is a risk factor for the development of schizophrenia.

Risk factor?

The link between cannabis use and psychosis has been known for over a hundred years. There is extensive evidence to show that cannabis use can cause a series of transitory psychotic symptoms, such as delirious or paranoid ideas, auditory and visual hallucinations, persecution complexes, etc., all of which are similar to the symptoms observed in schizophrenia. Some authors have suggested that this acute transitory psychosis induced by cannabis could be the antecedent of schizophrenia itself, or of the so-called prodromal symptoms which precede onset of the disease.

Nonetheless, it seems clear that there is no direct causal relationship between cannabis use and the onset of schizophrenia, given that the prevalence of the disorder is similar in very different regions and cultures, with different rates and patterns of cannabis use. Moreover, despite a significant increase in cannabis use in recent decades, the prevalence and incidence of schizophrenia has not varied substantially. Finally, only a small proportion of cannabis users go on to develop schizophrenia. One could also express the relationship inversely: most schizophrenia patients have never consumed cannabis.

On the other hand, there is abundant evidence pointing to the existence of an association amongst certain individuals between large-scale cannabis consumption and a greater risk of suffering schizophrenia. Several epidemiological studies have shown that cannabis users are 1.4 times more at risk of developing schizophrenia than non-users. This risk rises further, to 2.1 times, amongst those who frequently consume large quantities of cannabis. The general conclusion drawn by meta-analyses of these studies is that the association between cannabis use and schizophrenia is slight to moderate.

This relationship might also be mediated by the coexistence of other factors of vulnerability to development of the disorder such as use of other substances of abuse, low socio-economic level or a family history of schizophrenia. In this regard, it has been suggested that among people with a certain genetic vulnerability to the development of schizophrenia cannabis use might substantially increase the risk, advance onset and result in a worse course of the disorder with a more serious symptomatology and a poorer response to pharmacological treatment. Many studies also indicate that the first psychotic episode can be brought forward by several years by cannabis use. Depending on the population studied, this advance has been found to be in the order of 3 to 7 years. A study on a Spanish population also confirmed this advance in age of first psychotic treatment, observing a correlation with frequency of cannabis use. Additionally, it has been found that the onset of schizophrenia is earlier amongst male cannabis users than females. Some authors have suggested that this difference may be due to earlier cannabis use among males.

One of the conclusions that can be drawn from the epidemiological studies, is that early consumption of cannabis during adolescence, increases the risk of the schizophrenia and/or psychotic symptoms appearing in adulthood. Adolescent cannabis users who develop schizophrenia may also have a worse prognosis with earlier onset of the disorder, greater psychopathology, an increase in relapses, and a greater probability of failure of antipsychotic treatment. Both the cannabinoid receptors and endocannabinoids themselves appear in early stages of the development of the brain, and appear to be involved in processes of synaptogenesis in neural networks during this cerebral development. The endocannabinoid system has been shown to play a significant part in neural development, mainly through its role in modulating the release of the neurotransmitter glutamate. Through the activation of CB1 cannabinoid receptors, cannabis might interfere with these normal physiological processes, causing alterations in the release of glutamate which would induce mild neurotoxic effects and consequent structural defects. Maturation of the prefrontal cortex is one of the most important processes of adolescence and it is possible that cannabis use during this critical period of development especially affects the processes of consolidation of certain neurocircuits in this region of the brain. This process of abnormal maturation induced by cannabis use in adolescence could be the reason for the greater risk of developing schizophrenia in adulthood, especially amongst subjects with a greater genetic predisposition to the disorder.

Whatever the role played by cannabis use in the onset of schizophrenia, it seems clear that continued cannabis use after a diagnosis of schizophrenia is associated with greater incidence and severity of positive symptoms and poorer general functioning. In contrast, quitting consumption improves depressive symptoms and anxiety levels, reduces the psychotic symptoms and generally leads to better psychosocial functioning by the patient. It is therefore important to stress the idea that giving up cannabis use may be useful in favouring the treatment and evolution of patients with schizophrenia. That said, in some cases, cannabis use may actually constitute a form of self-medication, intended to reduce the symptoms of the disease or the adverse side-effects of pharmacological treatment.

Could some of the components of cannabis be a therapeutic alternative for treating schizophrenia?

At present, the pharmacological treatment of schizophrenia is based on the use of antipsychotic drugs. These are very effective in reducing the positive symptoms of schizophrenia but their effectiveness is very limited when it comes to controlling negative and cognitive symptoms. Moreover, they tend to have major adverse effects (extrapyramidal or Parkinsonian symptoms, weight increase, metabolic syndrome, etc.), and 20% of patients experience no improvement whatsoever following administration. As a result, there has been a growing focus in recent years on the endogenous cannabinoid system as a possible new therapeutic target for schizophrenia treatment. This is essentially because of the homeostatic role it plays in neurotransmission in the brain and in inflammatory processes. Moreover, various alterations of the endogenous cannabinoid system have been identified in schizophrenia patients. Some authors have therefore suggested that it might be of therapeutic use to modulate endocannabinoid levels using cannabidiol phytocannabinoids. A number of clinical trials are currently underway to assess the antipsychotic properties of cannabidiol in schizophrenia patients. Unfortunately, few data have yet been published on these studies into the antipsychotic effects of cannabidiol. However, there is initial evidence to suggest that cannabidiol might improve symptoms and have fewer adverse effects than the antipsychotics currently used to treat schizophrenia.

The first case of cannabidiol treatment (up to 1500 mg/day) improving the symptoms of a schizophrenia patient resistant to antipsychotic treatment was published in 1995. Since then, several clinical trials have been launched to gauge the effectiveness of cannabidiol in patients with schizophrenia. One of the first to be published compared the effectiveness of cannabidiol to that of the antipsychotic amisulpride over a 4-week period. Both compounds produced a significant clinical improvement with comparable antipsychotic effectiveness. The cannabidiol had fewer adverse effects than the amisulpride (it did not increase prolactin levels or cause weight gain or extrapyramidal symptoms). At least two more clinical trials are now underway. One compares the effect of cannabidiol to a placebo, and the other compares cannabidiol to a placebo as a coadjutant in patients treated with the antipsychotic risperidone. Summing up, the data currently available on the antipsychotic effects of cannabidiol are still limited, although the results so far are promising.

And while it is important to avoid the sort of social alarm that tends to see cannabis use as being uniquely responsible for triggering schizophrenia, we should not ignore the influence it can have in a vulnerable population. Cannabis use needs to be taken into consideration, with particular care among vulnerable subjects and adolescents. Preventative education is required to try to delay the start of cannabis use as long as possible in order to minimise its risk of contributing to the appearance of serious diseases in adulthood.

References:

1. Erdozain A.M.; Muguruza C.; Meana J.J.; Callado L.F. ¿Es realmente el consumo de cannabis un factor de riesgo para la esquizofrenia? Norte de Salud Mental 34:23-33 (2009).

2. Leweke F.M.; Mueller J.K.; Lange B.; Rohleder C. Therapeutic Potential of Cannabinoids in Psychosis. Biological Psychiatry 79:604-12 (2016).

3. Manseau M.W.; Goff D.C. Cannabinoids and Schizophrenia: Risks and therapeutic potential. Neurotherapeutics 12:816-24 (2015).

4. Urigüen L.; García Bueno B.; Leza J.C.; Callado L.F. Cannabinoides y trastornos mentales. En: "Efectos terapéuticos de los cannabinoides". Instituto Universitario de Investigación en Neuroquímica. Universidad Complutense de Madrid, pp 139-153 (2017).

5. Zuardi A.W.; Morais S.L.; Guimaraes F.S.; Mechoulam R. Antipsychotic effect of cannabidiol. Journal of Clinical Psychiatry 56:485-86 (1995).