Cannabinoids and Schizophrenia : Risks and Therapeutic Potential, Marc W. Manseau & Donald C. Goff, 2015

Cannabinoids and Schizophrenia : Risks and Therapeutic Potential

Marc W. Manseau & Donald C. Goff

Neurotherapeutics, 2015, 12, 816–824

DOI 10.1007/s13311-015-0382-6

# The American Society for Experimental NeuroTherapeutics, Inc. 2015



A convergence of evidence shows that use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at which psychotic symptoms first manifest. Cannabis exposure during adolescence is most strongly associated with the onset of psychosis amongst those who are particularly vulnerable, such as those who have been exposed to child abuse and those with family histories of schizophrenia. Schizophrenia that develops after cannabis use may have a unique clinical phenotype, and several genetic polymorphisms may modulate the relationship between cannabis use and psychosis. The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia. Anandamide signaling in the central nervous system may be particularly important. Δ9- Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects. CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have antiinflammatory and neuroprotective properties. Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research.

Key Words : Cannabinoids . schizophrenia . psychosis . cannabidiol . cannabis . endocannabinoid


Schizophrenia is a chronic and often disabling developmental brain disease that affects approximately 1 % of the population over the course of life [1], and is characterized by positive symptoms (delusions, hallucinations, and disorganized thinking), negative symptoms (social withdrawal, amotivation, and affective flattening), deficits in cognition (memory, executive functioning, and processing speed), and a decline in social and occupational functioning [2]. While significant advances have been made in understanding the neurobiology of schizophrenia, and effective treatments have been developed for positive symptoms, the goal of reversing disability associated with cognitive deficits and amotivation has not been realized.

Cannabis sativa is the most commonly used illicit substance globally, and its main psychoactive component, Δ9- tetrahydrocannabinol (THC), has been widely recognized for its ability to cause acute psychotic symptoms and cognitive impairment similar to schizophrenia [3, 4]. Cannabis is also the most commonly abused illicit substance amongst people with schizophrenia, and there is substantial evidence that continued use after a schizophrenia diagnosis is associated with worsening psychotic symptoms, relapse, and decreased functioning over time [4, 5]. Furthermore, epidemiologic evidence has accumulated implicating cannabis use as an important environmental risk factor for developing schizophrenia. In 1987, Andreasson et al. [6] reported that heavy cannabis use was associated with a 6-fold increase in risk for schizophrenia, based on a 15-year follow-up of Swedish military conscripts. Debate has since ensued over whether this association is causal. A greater understanding of the endocannabinoid system (ECS) and its links to psychosis has the potential to generate new insights into the neurobiological causes of schizophrenia, and to open up novel and more efficacious treatment options for this debilitating illness.

Here, we first review the evidence for cannabis use as a causal factor for the development of schizophrenia. Next, we review the biology of the ECS as it pertains to psychosis. Finally, we review preliminary evidence for the use of cannabinoid-based compounds in the treatment of psychosis, and identify potential future research directions for the field.

Cannabis and Schizophrenia


Vulnerability Factors


Gene-by-Environment Interactions


The ECS and Psychosis


Cannabinoids and Treatment