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 Δ-tetrahydrocannabinol (Δ-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.

Extension of the Theory of Planned Behavior (TPB) to Predict Patterns of Marijuana Use among Young Iranian Adults

“…This endocannabinoid system is functional from the early developmental stages and throughout adolescent cortical development. Schonhofen et al [27] also observed that the endocannabinoid system, among others, regulates progenitor cell fate, neural differentiation, migration, and survival. Given this, it is not surprising that the endocannabinoid system may be particularly vulnerable to excessive cannabinoid exposure.…”

“…Such vulnerability appears to be related to the greater sensitivity of the endocannabinoid system [26]. More specifically, Schonhofen et al [27], in their overview, noted the importance of the endocannabinoid retrograde signaling pathway in regulating both excitatory and inhibitory synaptic plasticity via long-term potentiation and long-term depression. Cannabinoid receptors, endocannabinoids, and synthesis or degradation enzymes form the endocannabinoid system (ECS).…”

Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy

“…However, long-term effects on cognition is one major concern with cannabinoid treatment (21). Longer observational periods and studies with a more detailed neurocognitive test protocol are needed.…”

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

“…) and endogenous arachidonic acid (AA)‐derived mediators, are synthesized from membrane phospholipids (Alswat ) and are directly involved in synaptic plasticity and cortical development (Schonhofen et al. ). The therapeutic potential of cannabinoids in seizures is well described (Perucca ; Rosenberg et al.…”