Cannabinoid-Based Therapies and Brain Development : Potential Harmful Effect of Early Modulation of the Endocannabinoid System
Patrícia Schonhofen, Ivi Juliana Bristot, José Alexandre Crippa, Jaime Eduardo Cecílio Hallak, Antônio Waldo Zuardi, Richard B. Parsons, Fábio Klamt
CNS Drugs, 2018, 32, (Suppl 1), 1-16.
Springer Nature Switzerland,
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.
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.
The plant Cannabis sativa has been used for medicinal purposes for thousands of years by different cultures . Cannabis extract contains more than 80 components, of which Δ9-tetrahydrocannabinol (Δ9-THC) (the main psychoactive ingredient) and cannabidiol (CBD) are the most abundant [2, 3]. These compounds were first identified several decades ago , but it is only more recently that the discovery of cannabinoid receptors and their endogenous homologues, the endocannabinoids  such as N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) , has occurred. Together with their related enzymes, endocannabinoids and their receptors form the endocannabinoid system (ECS) (Fig. 1) . Cannabinoids—both endogenous and plant derived—target the G protein coupled cannabinoid receptor type 1 ( CB1), which is widely expressed in the nervous system, and cannabinoid receptor type 2 ( CB2), which is mainly expressed in immune cells [8, 9]. Presently, it is proposed that the ECS has roles in the pathological mechanisms of several psychiatric disorders, including schizophrenia . Besides, cannabinoids such as CBD also interact with a variety of non-endocannabinoid mechanisms, including numerous classical ion channels, receptors, transporters, and
enzymes, as reviewed recently .
The effects of isolated cannabinoids and Cannabis extracts in different diseases have been studied for many years . In the United States, recent medical and recreational marijuana legalization increased Cannabis accessibility and use . Additionally, despite widely known deleterious effects during central nervous system development, medical marijuana usage by minors, with the consent from a legal guardian and certification from a physician, is approved . Marijuana-derived products have their main effects against childhood severe epilepsies, including Dravet and Lennox-Gastaut syndromes. These early onset disorders are characterized by frequent, refractory seizures and neurodevelopmental
delays, which lead to impaired quality of life in these individuals. This scenario compels families to seek alternative treatment methods, such as CBD-based therapies, which include pure synthetic or plant-derived CBD and CBD-enriched Cannabis extracts. In children, plantderived, pharmaceutical-grade isolated CBD has been tested in clinical trials in patients with such syndromes [15–17], and this drug ( Epidiolex®) has recently been approved in the USA as an orphan drug for those syndromes. Clinical trials with synthetic isolated CBD are ongoing (clinicaltrials.gov website). In addition, reports on the use of different forms of Cannabis extracts in children with epilepsy have also been published [18–20]. However, only few adequately powered, placebo-controlled, randomized studies have evaluated the safety and efficacy of CBD-based therapies in children . Nevertheless, most of these therapies have been reported to have a greater reduction in convulsive seizure frequency than placebo, being associated, however, with higher rates of adverse events .
The constituents of the ECS, receptors and endocannabinoids, are expressed and are functional from very early developmental stages, whereby they regulate inhibitory and excitatory synapses. Even during adolescence, the brain and the ECS undergo active development, which may confer increased vulnerability to adverse long-term outcomes from early cannabinoid exposure . Endocannabinoids
have been shown to regulate cortical development throughout life in humans, and exogenous cannabinoids can alter cortical development of both the somatosensory and the
prefrontal cortex .
Nevertheless, the current widespread use of CBD-based therapies in children and young adults, without sufficient studies on the potential consequences regarding neuronal and other systems’ development, is of concern to the scientific and medical communities. One area of particular concern is the uncontrolled amount of Δ9-THC present in such extracts. Moreover, in 2017, an ad hoc committee of the National Academies of Sciences, Engineering, and Medicine presented a report regarding the health effects of Cannabis to either support or refute the use of such compounds as an effective treatment for epilepsy . Hence, this article reviews the current knowledge about the use of CBD-based therapies in pediatric patients, the alleged side effects, and the mechanisms of action regarding the central nervous system and neurodevelopmental aspects. We highlight that CBD administration before adulthood must be carefully
evaluated, and the use of pure CBD and/or synthetic cannabinoids as a preferential alternative to Cannabis extracts for children and young adults needs to be studied further.
2 The Endocannabinoid System
Most cannabinoids exert their therapeutic properties upon the central nervous system primarily via the ECS, although there are other known targets . Here, we discuss their effects upon the ECS. Endocannabinoid signaling plays crucial roles in various aspects of both the underdeveloped and the mature brain . Therefore, disturbances in this system may disrupt neural development.
The classical ECS signaling pathway is shown in Fig. 1 (for review see ). In the mature brain, the ECS modulates synapses (excitatory and inhibitory) through the release of endocannabinoids AEA and 2-AG. These act as retrograde messengers, their release by the postsynaptic neuron activating CB1
receptors in the pre-synaptic neuron, leading to decreased release of neurotransmitters into the synaptic cleft [10, 28, 29]. This process is initiated by increased Ca2+ influx caused by neurotransmission in the postsynaptic neuron, which activates endocannabinoid synthesis from its precursors in the plasma membrane. AEA is generated from phospholipase D-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE), while 2-AG originates from the diacylglycerol lipase-mediated hydrolysis of diacylglycerol (DAG), derived mainly from membrane-localized phosphatidyl-inositol biphosphate (PIP2). AEA and 2-AG diffuse towards the pre-synaptic terminals and, like exogenous cannabinoids such as Δ9-THC, bind to and activate the pre-synaptic, G protein-coupled CB1
receptors. This binding triggers the activation and release of Gi/Go proteins from the CB1, inhibiting adenylyl cyclase (AC) and thus decreasing cyclic adenosine monophosphate (cAMP) formation and subsequent protein kinase A (PKA) activity. These events lead to opening of inwardly rectifying K+ channels, causing a hyperpolarization of the pre-synaptic terminal, and closing of Ca2+ channels, arresting the release of stored neurotransmitters. Finally, AEA and 2-AG re-enter the post- or pre-synaptic terminals, where they are catabolized respectively by fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), to yield either arachidonic acid (AA) and ethanolamine (ET) in the case of AEA, or AA and glycerol for 2-AG. The transport of endocannabinoids through the plasma membrane is still not completely understood. Although some studies have proposed the existence of an endocannabinoid transporter, the trafficking of AEA, which has been most extensively studied, is proposed to occur through facilitated membrane transport followed by intracellular shuttling and sequestration .