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.

Key Points

Cannabidiol (CBD) targets the endocannabinoid system directly via cannabinoid receptor type 1 (
CB1) receptors or indirectly by regulating endocannabinoid levels, in both developing and mature brains.

Δ9-Tetrahydrocannabinol (Δ9-THC) is believed to be responsible for the majority of the potential harmful effects of CBD-enriched Cannabis extracts, although further direct evaluation of the effects of CBD upon brain development is necessary.

For young patients, pure CBD, both synthetic or plant derived, produced in accordance with good manufacturing practices (GMP-grade), is recommended as a therapeutic option instead of CBD-enriched Cannabis extracts, and a recently CBD-based product ( Epidiolex®) was approved by the Food and Drug Administration (FDA) for the treatment of Dravet and Lennox-Gastaut syndromes.

There is a lack of trials of chronic administration of CBD-based therapies with long-term follow-up periods; conducting such trials would allow a more realistic comparison of the effects of these therapies with those of current treatment options.

(…)