Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System

Abstract

The endocannabinoid retrograde signaling pathway is widely expressed in the central nervous system, where it plays major roles in regulating synaptic plasticity (excitatory and inhibitory) through long-term potentiation and long-term depression. The endocannabinoid system (ECS) components—cannabinoid receptors, endocannabinoids and synthesis/degradation enzymes—are expressed and are functional from early developmental stages and throughout adolescent cortical development, regulating progenitor cell fate, neural differentiation, migration and survival. This may potentially confer increased vulnerability to adverse outcomes from early cannabinoid exposure. Cannabidiol (CBD) is one of the most studied exogenous cannabinoids, and CBD-enriched Cannabis extracts have been widely (and successfully) used as adjuvants to treat children with refractory epilepsy, and there is even a Food and Drug Administration (FDA)-approved drug with purified CBD derived from Cannabis. However, there is insufficient information on possible long-term changes in the central nervous system caused by cannabinoid treatments during early childhood. Like the majority of cannabinoids, CBD is able to exert its effects directly and indirectly through the ECS, which can perturb the regulatory processes mediated by this system. In addition, CBD has a large number of non-endocannabinoid targets, which can explain CBD’s effects. Here, we review the current knowledge about CBD-based therapies—pure and CBD-enriched Cannabis extracts—in studies with pediatric patients, their side effects, and their mechanisms of action regarding the central nervous system and neurodevelopment aspects. Since Cannabis extracts contain Δ9-tetrahydrocannabinol (Δ9-THC), we consider that pure CBD is possibly safer for young patients. Nevertheless, CBD, as well as other natural and/or synthetic cannabinoids, should be studied in more detail as a therapeutic alternative to CBD-enriched Cannabis extracts for young patients.

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Acknowledgements

AWZ, JECH, FK and JAC are recipients of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil). This review was supported by the Brazilian funds CNPq/MS/SCTIE/DECIT Pesquisas Sobre Doenças Neurodegenerativas (466989/2014-8), CNPq/MS/SCTIE/DECIT No 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos (466805/2014-4) and INCT-TM/CNPq/FAPESP (465458/2014-9). PS wishes to acknowledge Marco Antonio de Bastiani, MSc for helpful comments made during the preparation of the manuscript.

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Correspondence to Fábio Klamt.

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Funding

This review was supported by the Brazilian funds CNPq/MS/SCTIE/DECIT Pesquisas Sobre Doenças Neurodegenerativas (466989/2014-8), CNPq/MS/SCTIE/DECIT N 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos (466805/2014-4) and INCT-TM/CNPq/FAPESP (465458/2014-9). AWZ, JECH, FK and JAC are recipients of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil).

Conflict of interest

AWZ, JECH and JAC are co-inventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US no. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JECH and JAC have received travel support from and are medical advisors of BSPG-Pharm. AWZ is medical advisor of BSPG-Pharm. PS, FK, IJB, RBP declare no conflics of interest.

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Schonhofen, P., Bristot, I.J., Crippa, J.A. et al. Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System. CNS Drugs 32, 697–712 (2018). https://doi.org/10.1007/s40263-018-0550-4

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