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Eur J Pain. 2019 Aug;23(7):1225-1233. doi: 10.1002/ejp.1377. Epub 2019 Mar 19.

Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders.

Krebs MO1,2,3, Kebir O1,2,4, Jay TM1,2.

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Inserm, Laboratoire de Physiopathologie des maladies Psychiatriques, UMR_S1266 Institut de Psychiatrie et Neurosciences de Paris, Université Paris Descartes, Paris, France.
Institut de Psychiatrie (CNRS GDR 3557), Paris, France.
Faculté de Médecine Paris Descartes, Service Hospitalo Universitaire, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Paris, France.
Service d'Addictologie «Moreau de Tours», Centre Hospitalier Sainte-Anne, Paris, France.



Cannabinoids are proposed in a wide array of medical indications. Yet, the evaluation of adverse effects in controlled clinical studies, following the evidence-based model, has partly been bypassed. On the other hand, studies on the consequences of recreational use of cannabis and experimental studies bring some insights on the potential long-term consequences of cannabinoids use.


Epidemiological studies have consistently demonstrated that cannabis use is associated with a risk of persistent cognitive deficits and increased risk of schizophrenia-like psychoses. These risks are modulated by the dose and duration of use, on top of age of use and genetic factors, including partially shared genetic predisposition with schizophrenia. Experimental studies in healthy humans showed that cannabis and its principal psychoactive component, the delta-9-tetrahydrocannabinol (THC), could produce transient, dose-dependent, psychotic symptoms as well as cognitive effects, which can be attenuated by cannabidiol (CBD). Studies in rodents have confirmed these effects and shown that adolescent exposure results in structural changes and impaired synaptic plasticity, impacting fronto-limbic systems that are critically involved in higher brain functions. The endocannabinoid system plays an important role in brain maturation. Its over-activation by cannabinoid receptor type 1 agonists (e.g., THC) during adolescence and the resulting changes in neuroplasticity could alter brain maturation and cause long-lasting changes that persist in the adult brain.


Exposure to cannabinoids can have long-term impact on the brain, with an inter-individual variability that could be conveyed by personal and family history of psychiatric disorders and genetic background. Adolescence and early adulthood are critical periods of vulnerability.


The assessment of benefice-risk balance of medical use of cannabis and cannabinoids needs to carefully explore populations that could be more at-risk of psychiatric and cognitive complications.


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