Complex movement disorders are a heterogeneous group of neurological disorders characterized by different types of abnormal movements and postures, including spasticity and dystonia. These abnormal movements and postures are generally associated with severe orthopedic problems, chronic pain, eating difficulties, constipation, sleep disturbances, epilepsy, and a poor quality of life. ^{( 1 )} Cerebral palsy (CP) is the most common complex movement disorder, with multiple complications that begin during childhood. The estimated prevalence is 2–3 per 1,000 live births. ^{( 2 )} Medical cannabinoids are becoming increasingly popular in several countries. Cannabinoid-based therapies have been investigated for the treatment of various neurological disorders, particularly drug-resistant epilepsy and movement disorders. ^{( 3 )} The methodologies used in these studies and the derived results are controversial. Cannabinoid-based drugs, phytocannabinoids, and synthetic cannabinoids have multiple mechanisms of action including interactions with endocannabinoid receptors. ^{( 4 , 5 )} In addition, cannabidiol may potentiate some of the beneficial effects of tetrahydrocannabinol (THC) as it reduces the psychoactivity of THC and allows patients to tolerate higher THC doses. Cannabidiol may also complement the anti-spasmodic effects of THC ( e.g ., via local enhancement of glycine signaling; inhibition of endocannabinoid degradation; or delayed demyelination through anti-inflammatory, antioxidant, and anti-excitotoxic mechanisms). ^{( 5 )} Cannabinoids have therapeutic potential in movement disorders. Synthetic cannabinoids, such as nabilone, dronabinol, and Sativex, are cannabinoid receptor agonists with effects similar to those of THC. They have been approved for clinical indications including spasticity, pain, and refractory epilepsy. ^{( 6 , 7 )} However, its efficacy and safety in children with CP are uncertain, especially in the treatment of spasticity, pain, and seizures. This systematic review aimed to assess the efficacy and safety of medical cannabinoids in children with CP.

Reports on the benefits of medical cannabis are increasing. Despite the controversy over its safety and efficacy, studies have suggested that cannabis may have the therapeutic potential to improve several disorders, including neurological diseases. ¹⁴ Reduction in seizure frequency, ^{( 17 , 18 )} spasticity, neuropathic pain, ^{( 15 )} and other motor function disorders ^{( 16 , 18 )} are the most-reported positive impacts.

However, concerns regarding the adverse effects of cannabis have emerged. Non-serious adverse effects may occur even before cannabis initiation. ¹¹ However, they can be generally resolved by reducing the dose of cannabis or changing the pattern of administration. ^{( 12 , 16 , 17 )} THC is the most important contributor to the psychoactive side-effects. Using a ‘start low and go slow’ dosing strategy and combining CBD with THC may mitigate most adverse events. ^{( 19 )} Therefore, the safety level is generally acceptable if the medication dose and administration are suitable.

Cannabis plants contain more than 100 known cannabinoid compounds. The psychoactive Δ9-tetrahydrocannabinol (Δ9-THC) and the non-psychoactive CBD are the principal neuroactive components of cannabis. The term “non-psychoactive” refers to the absence of psychotropic effects compared to Δ9-THC. ^{( 20 )} Most cannabis retail products fall into one of the following three categories: Δ9-THC-dominant, CBD-dominant, or a balanced “hybrid” product with high concentrations of both Δ9-THC and CBD. ^{( 21 )} These products can be consumed through several methods, including smoke inhalation, vaporization, oral ingestion, and other routes (topical and suppository). ^{( 19 )} All three included studies reported on oral-ingestion of various preparations of cannabis, such as oils, tinctures, and sprays, which are associated with better convenience and less odor. ^{( 22 )}

Cerebral palsy refers to a set of persistent movements and postural disorders that restrict activity and is caused by non-progressive disruptions in the developing brain. ^{( 23 )} This disorder causes motor disorders, a broad range of comorbidities, and secondary conditions such as sensation, perception, cognition, communication, and behavioral disturbances. ^{( 24 )} Pain is the most common secondary consequence of severe health concerns in children with CP. It is primarily related to movement disorders (the basis of CP), musculoskeletal problems, and repeated exposure to painful procedures, including surgery. ^{( 25 )}

The effect of cannabinoid administration in patients with CP is uncertain despite its high potential. ^{( 26 )} There are two types of cannabinoid receptors in human cells: types 1 (CB1) and 2 (CB2). CB1 is found in the central nervous system and peripheral tissues, whereas CB2 is mainly found in the immune cells. ^{( 27 )} CB1 receptors are primarily located at the terminals of the central and peripheral neurons, where they regulate neurotransmitter release and psychoactive traits. They are also abundant in brain areas associated with nociceptive perception, such as the thalamus and amygdala. ^{( 28 )} CB1 receptor activation modifies nociceptive thresholds and exerts various biological effects by balancing excitatory and inhibitory neurotransmitters, mainly related to the Gamma-Aminobutyric Acid system, which can be used to treat seizures and spasms. ^{( 29 , 30 )} CB2 receptor activation hinders the release of inflammatory mediators by cells close to the nociceptive nerve terminals and prevents pain signals from entering the central nervous system. ^{( 28 )}

Cannabinoids presynaptically hinder glutamate release. ^{( 31 )} The amplification of CB1 receptors reduces glutamatergic transmission in THC-exposed animals, and chronic cannabis use decreases glutamate metabolites in the human brain. Several animal studies have identified CB1 as a receptor that modulates the anti-spasticity effects of cannabinoids. ^{( 28 )} Owing to its effectiveness in alleviating spasticity in both animal models and humans, Δ9-THC is the most important cannabinoid that mediates the anti-spasticity effect of cannabinoid preparations. ^{( 32 )} Therefore, Δ9-THC is responsible for treating CP-related dystonia.

In addition to lowering spasticity, Δ9-THC and CBD have been shown to prevent seizures in animal models. These substances exhibit low toxicity and high tolerability. ^{( 33 )} Δ9-THC is a partial agonist of both CB1 and CB2 receptors and reduces the severity of seizures by activating CB1. Furthermore, Δ9-THC has powerful anti-inflammatory effects on microglia, which are the primary immune cells of the central nervous system. Considering the synergistic relationship between seizures and inflammation, the cannabinoid system offers a novel strategy for targeting both sectors of this feedback mechanism. ^{( 34 )} Cannabidiol structurally resembles Δ9-THC, but has low affinity for CB1 and CB2 receptors. Cannabidiol may exert anti-seizure effects by reducing glutamate release. CBD also minimizes epileptiform events in the hippocampus in an in vitro model in a CB1-independent, concentration-dependent, and region-specific manner. ^{( 35 )} The illustration of the effects of cannabinoids on spasticity and epileptic seizures is shown in figure 3 .

This systematic review has some limitations. The number of studies included in this systematic review was limited to those with different study designs. Of the three studies, only one was an RCT. The small sample sizes of the included studies may not represent real-world efficacy and safety. In addition, the study focused mainly on the European population, making generalizability challenging to achieve.

Cannabinoids may be beneficial in patients with cerebral palsy; however, their effectiveness has yet to be thoroughly studied. The proposed modes of action of cannabinoids in cerebral palsy include anti-spasticity, anti-inflammatory, and anti-seizure features. Although mild-to-moderate adverse events have been reported, there have been no reports of long-term adverse events, indicating a favorable safety profile. Further research with a larger sample size, extended study period, and individuals of various ethnicities is required to determine the role of cannabinoids in cerebral palsy.