Cannabis Compounds: Potential Therapy for Neurological Disease

Abstract

Identification and development of pharmaceuticals for neurological disorders is associated with several unique challenges. The primary weakness of candidate neurological compounds is the poor penetration efficacy across the blood-brain barrier (BBB). The BBB is the bottleneck in nervous system drug development and is the paramount factor that limits success in neurotherapeutics. Findings suggest cannabinoids might overcome the limiting effects of the BBB and play a key role in improving neurological dysfunctions. This supports the therapeutic potential of cannabidiol for the treatment of ischemic and inflammatory diseases of the central nervous system (CNS). The potential application of cannabinoids for Parkinson’s disease, Autism, and childhood Epilepsy is explored in this chapter.

1. Introduction: ethnobotanical aspects of Cannabis sativa

Geographically, Central Asia and South-East Asia are believed to be the regions of origin for Cannabis sativa. Various forms of C. sativa were identified in medieval Europe, however, Cannabis was unknown in the Americas until the arrival and settlement of the European colonists. In the 18th century Carl Linnaeus, a Swedish botanist introduced the name Cannabis sativa. The primary use of the plant historically was in textile manufacturing. Of note, the psychotropic application of the plant was in fact discovered by accident. In the 19th century, medical applications for treating pain and inflammation were introduced. More recently, there has been extensive interest in the medical use of cannabis for pain, gastrointestinal disorders, anti-microbial, multiple sclerosis (MS), nausea and vomiting, anorexia, sleep disorders, anxiety, Tourette syndrome, and several neurological diseases—epilepsy, Parkinson’s, autism, and Alzheimer’s.

Over 500 compounds have been identified in Cannabis sativa of which approximately 100 have been characterized as phytocannabinoids. The phytocannabinoid composition of C. sativa is influenced by environmental conditions including humidity, temperature, ultraviolet radiation, soil nutrients, and parasites. Phytocannabinoids include the neutral cannabinoids (absence of carboxyl group) and the cannabinoid acids (presence of carboxyl group). The phytocannabinoids are segmented into 10 subclasses as shown in Figure 1. Trans-∆-9-tetrahydrocannabinol is the primary C. sativa associated with psychoactive effects including anxiety, paranoia, perceptual alterations, and cognitive deficiency. Cannabidiol (CBD) is the most abundant phytocannabinoid in Cannabis species cultivated for textile use.

Figure 1.

Chemical structures of primary natural cannabinoids.

2. Cannabinoids

Neurological disorders are a group of illnesses influencing the central and peripheral nervous systems. Depending on the part of the nervous system, a person may experience difficulties with movement, sensations, breathing, speech, learning, memory, mood, and more. Triggers of neurological conditions are genetic disorders, congenital abnormalities, infections, and brain injuries.

Recently, cannabis and its substances (cannabinoids) began using as therapeutic agents in some disease states [1]. CBD and delta-9-tetrahydrocannabinol (THC) are the most researched compounds found in cannabis plants. The effects of CBD and THC on the body are different. THC is psychoactive and affects mood, perception, and other mental processes. THC also has neuroprotective, analgesic, antiemetic, and antiglaucoma impacts [2, 3]. CBD is a nonpsychoactive ingredient and exhibits anti-inflammatory, antioxidant, anticonvulsant, and neuroprotective effects as well as decreases the THC psychoactivity [4, 5]. Epidiolex, a pharmaceutical grade-CBD, is used to treat seizures of Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. Sativex containing CBD (50%) and THC (50%) is employed to treat multiple sclerosis [1]. THC-containing medications, dronabinol, and nabilone are utilized for chemotherapy-induced nausea and vomiting as well as for anorexia in AIDS patients [6]. Another cannabinoid, cannabidivarin (CBDV) also manifests the medicinal effects of cannabis. CBDV is similar to CBD structurally and functionally. CBDV is a nonpsychotropic phytocannabinoid with anti-inflammatory and anticonvulsant activities [7]. Recently, the FDA and EMA granted an orphan designation to CBDV for both fragile X and Rett syndromes.

The cannabinoids interact with is the endocannabinoid system (ECS). The ECS controls some biological operations and incorporates the endocannabinoids, the cannabinoid receptors, and the endocannabinoid enzymes. Endocannabinoids, ECBs assist in regulation of memory, pleasure, concentration, thinking, movement and coordination, sensory and time perception, and pain [8]. Endocannabinoids are produced by cultured neurons, microglia, and astrocytes [9]. The key ECBs are arachidonoyl ethanolamide (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG) [9]. The ECBs activate the G-protein coupled (GPR55), the cannabinoid 1 (CB1) and 2 (CB2) receptors [10]. AEA has agonistic action on TRPV1 as well [11]. CB1 is mostly localized in the central and peripheral nerve cells, specifically in glutamatergic and gamma-aminobutyric neurons and is responsible for the neurotransmitter release [12, 13]. The CB2 receptors were primarily detected in the immune system: T and B cells and macrophages [8]. CB2 was also found in the brain microglial cells and in peripheral nerves [8]. Both CB1 and CB2 were also discovered in cardiovascular, reproductive, and gastrointestinal systems. Levels of endocannabinoids, AEA and 2-AG are controlled by enzymes. N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) modulate synthesis of the endocannabinoids, while fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are responsible for their degradation [1].

Cannabinoids interact with ECS in the body. THC relates to CB1, CB2, and GPR55 receptors as a partial agonist [4]. THC administration creates an overexcitation of the endocannabinoid system that results in altered perceptions, pleasure, and mood [8]. CBD exhibits just minor attraction to CB1 and CB2 and functions as an indirect antagonist of cannabinoid agonists and inverse CB2 agonist [4]. CBD was connected to indirect modulation of the CB1 and CB2 via FAAH inhibition, which results in increased levels of agonist AEA [14]. CBD might also interact with GPR55, TRPV, TRPA, and TRPM [15]. CBD functions as an agonist of TRPVs and as an antagonist of GPR55 [16, 17, 18].

3. Parkinson’s disease

Research results suggest the key role of the endocannabinoid system in Parkinson’s disease (PD). Endocannabinoids contribute a major role in regulating transmission at synapses between cortical and striatal neurons, in influencing basal ganglia activity, and in controlling the induction of a particular form of synaptic plasticity and motor functions [19]. PD patients have an evolving deficiency of dopaminergic nerve cells leading to decreased striatal dopamine concentrations, which in turn produces variations of the balance related to basal ganglia paths and endocannabinoid signaling [8]. The endocannabinoid signaling manifests two-phase alterations in the evolution of this disease [20]. Premature phases are correlated with CB1 desensitization and downregulation as well as with aggravation of excitotoxicity, oxidative stress, and glial activation [21]. More progressive phases with deeper nigral deterioration have up regulatory reactions of CB1 ligands [21]. PD laboratory animals had enhanced CB1 density and concentrations of endogenic ligands, both of which led to increased basal ganglia CB1 binding [8]. Further signs of a major position of ECS in PD entail inhibition of the neurotransmitters by cannabinoids and deviations in the endocannabinoid’s transmission [8, 22]. These findings may define CB1 as a therapeutic target in easing PD signs.

An additional receptor controlling movement and interacting with ECS is TRPV1, which was found in sensory neurons and basal ganglia circuitry of dopaminergic neurons [23]. AEA is one of the key activators of TRPV1 [24, 25]. Several investigations reported that motor behavior could be controlled by the activation of TRPV1 [26, 27], suggesting that this receptor might play a role in the control of motor function.

3.1 Endocannabinoid system in Parkinson’s disease

The correlation of the ECS with motor functions was well confirmed. Studies have shown that not only endocannabinoids but also synthetic and plant-derived cannabinoids regulate the ECS and exert a powerful motor effect [8, 24]. Activation of CB1 receptors in neurons of the basal ganglia mediated a hypokinetic effect [28, 29, 30, 31]. In animal PD model cannabinoid HU-210 reduced glutamatergic activity and decreased pharmacologically induced spins by interaction with CB1 [32, 33]. THC and synthetic cannabinoids WIN 55,212–2 and CP 55,940 elevated dopamine levels and diminished contralateral rotations in PD rats [8]. THC generated increased tyrosine activity in parkin-null animals and emitted motor inhibition, catalepsy, antinociception, and ring immobility in other animal models [8]. Additional animal studies reported that THC decreased the motor disfunction triggered by 6- hydroxydopamine and intensified the hypokinetic impact of reserpine [34, 35]. However, THC has not influenced motor function in PD primates [36]. Conversely, the synthetic agonist levonantradol decreased general and locomotor activity and increased bradykinesia in a primate model of Parkinson’s disease [36]. WIN 55,212-2 demonstrated a dose-dependent reduction of the spontaneous motor activity and catalepsy in mutant Syrian hamsters and markedly reduced the anti-kinetic effects produced by quinpirole in reserpine animals [37]. WIN 55,212-2 has lowered levodopa-made dyskinesias, weakened axial, limb, and orolingual abnormal activities in 6-OHDA animals [38, 39]. Endocannabinoid agonist oleoylethanolamide, OAE developed lessening of involuntary rotary motions and reduction of molecular associates of induced dyskinesia [40]. Nabilone, a synthetic cannabinoid agonist, co-administered with levodopa significantly lowered total dyskinesia and extended the duration of antiparkinsonian action of levodopa in PD marmosets [41]. Endocannabinoid agonist AEA increased the extracellular dopamine levels in the nucleus accumbens shell of rats and induced hypokinesia [42]. Additionally, AEA constrained ambulation and stereotypical activities and blocked the influence of VR1 agonist livanil on motor functions [42]. Treatment with AEA reduced motor activity with the maximal inhibition by approximately 85% in mice and extended the inactivity time, lowered the ambulation and the frequency of spontaneous non-ambulatory activities in rats [8]. AEA also generated similar to THC decrease in impulsive motor activity in PD animals [8, 42].

Activities of AEA and 2-AG can be affected by inhibition of the FAAH enzyme. Studies have confirmed that FAAH inhibition remarkably increases AEA tissue level but reduces 2- AG level [43, 44]. Animal studies have shown that the FAAH enzyme inhibitor URB597 intensified and prolonged a dopamine increase produced by AEA [45]. Moreover, URB597 raised AEA blood concentrations, dropped the hyperactivity and prevented induced motor deficiency [46, 47]. Some other FAAH blockers (JNJ1661010 and TCF2) have anticataleptic ability as well [47]. In general, the findings indicate endogenous or exogenous cannabinoid agonists activate the dopaminergic system and play an important role in the regulation of motor behavior.

The CB1 receptor antagonists can also influence movement syndromes of Parkinson’s disease. In a study with PD rats and marmosets rimonabant (SR141716A), a selective antagonist of the CB1 receptor was functioning as a potential anti-hypokinetic agent [48, 49]. This compound blocked the THC impact on dopamine release and improved the locomotive movement in animals pre-exposed to THC [50]. SR141716A drastically reduced levodopa-induced dyskinesia, overturned the impact of the agonist WIN 55,212-2 and recovered the locomotive motions in PD animals [49, 51]. Administration of SR141716A dropped AEA and 2AG concentrations in the brain, promoted the locomotive power of quinpirole, and rebuilt movements in laboratory models [8, 49]. Moreover, SR141716A and additional CB1 receptor antagonist AM251 generated antiparkinsonian effects in rats with severe nigral degeneration [8, 52] (Fernandez-Espejo, 2005). A second CB1 antagonist, CE-178253, generated a 30% increase in motor behavior responses to L-DOPA in MPTP-treated rhesus monkeys [53]. THCV enabled modifications in glutamatergic transmission and reduced the motor obstruction [34]. Taken together, the discoveries advocate CB1 antagonists could be successful in controlling PD symptoms.

The activation of CB2 receptors may also contribute to the potential of cannabinoids in PD treatment [54]. CBD has also demonstrated significant effects in preclinical models of neurodegenerative disorders in combination with other cannabinoids [34, 55]. CBD and THCV, which is a CB2 partial agonist, reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra of PD rats [34]. The two compounds acted by means of neuroprotective and antioxidant mechanisms [34, 54], suggesting that CB2 receptor agonists may have a promising pharmacological profile for delaying disease progression. Therefore, CB1 antagonists may produce antiparkinsonian results, whereas CB agonists might be beneficial as a therapy of motor problems in PD.

3.2 Cannabinoids as a potential therapy for Parkinson’s disease

Cannabis and related compounds have generated a major research interest as a potential therapy in neurodegenerative and movement disorders. Cannabinoids have demonstrated healing properties in the management of Tourette, Huntington’s, and Parkinson’s disorders [8]. In a study with 339 PD patients, smoked cannabis created substantial upgrading of typical signs in almost half of the affected people. The patients noticed alleviation in resting tremor, rigidity, bradykinesia, and dyskinesias [56]. The same study connected high urine levels of 11-HO-THC (THC active metabolite) with decline of PD indications [56]. In other PD patients who smoked cannabis developed substantial positive transformation in tremor, rigidity, and bradykinesia [57, 58]. The dose and frequency of the cannabis administrations were key factors in relieving PD symptoms. A single smoked cannabis process resulted in tree-hours signs removal [58]. The investigations also demonstrated meaningful improvements in sleep and pain, which are common nonmotor PD signs [57, 58]. In contrast, PD patients and patients with levodopa-induced dyskinesia displayed no improvement after administration of oral cannabis extract [59].

Some reports described the impacts of CBD on Parkinson’s disease indicators. CBD reduced Unified Parkinson Disease Rating Scale (UPDRS) results and notably lowered signs of psychosis in PD individuals with psychotic disorder [60]. CBD ameliorated tremor and hypokinesia in patients with Parkinson’s disease [61]. However, in a second study CBD administration resulted in no improvement in measures of motor and general PD symptoms [62, 63]. Interestingly, in PD population CBD produced substantially different Parkinson Disease Questionnaire results compared to placebo treatment [62, 63].

More investigations were performed to examine cannabinoid nabilone. Nabilone has markedly alleviated abnormal involuntary movements in individuals with deep levodopa-induced dyskinesia [64, 65]. Nabilone was also effective against bradykinesia [64]. Other cannabinoid-associated substances CE178253, OEA, and HU-210 were also effective in treatment of levodopa-induced dyskinesia and bradykinesia [8, 66]. But the American Academy of Neurology (AAN) review deemed marijuana “probably ineffective” for treating L-DOPA-induced dyskinesia [67].

The impact of cannabis on dystonia was investigated as well. Cannabis generated significant alleviation of dystonia and pain lessening in dystonic patients with severe pain. The patients were able to withdraw opioids [68]. Cannabis eased idiopathic and generalized dystonia in patients with Wilson’s disorder [69]. CBD improved dystonia by 20–50% in dystonic patients and CBD withdrawal resulted in severe generalized dystonia in PD patients [8, 61]. Another cannabinoid, THC generated a reduction of abnormal movement patterns in patients with dystonia and athetosis [70].

The potential benefits of medical cannabis and cannabinoids for the treatment of another neurodegenerative disorder, Huntington’s disease (HD) has also been evaluated. A study reported that nabilone compared to placebo showed a treatment difference for total motor score, chorea, Unified Huntington’s Disease Rating Scale (UHDRS) cognition and behavior, and for the neuropsychiatric inventory in HD patients [71]. AAN recommended nabilone for moderate lessening of chorea in HD patients [72]. Research reports regarding CBD value in treatment of HD are lacking consistency. An investigation stated that CBD lowered chorea in 20–40% of patients with HD [73]. Conversely, more recent research did not verify this discovery [74]. CBD did not produce any meaningful results on chorea difficulty in HD individuals [74]. It was reported cannabis and THC may lessen tics and behavior conditions in patients with Tourette’s syndrome (TS) [75, 76, 77]. These patients informed consumption of cannabis/THC improved or in some cases completely revised motor and vocal tics as well as premonitory urges and obsessive-compulsive signs [76, 77].

Collectively, no powerful verification was obtained to suggest cannabis as a therapy for Parkinson’s disease. Though, prospective values were discovered in easing tremor, anxiety, pain, and sleep disorder [78]. Given the relative lack of investigations, there is a recognized necessity for additional well-designed studies.

4. Autism

Autism spectrum disorders (ASD) are neurodevelopment disorders characterized by difficulty in social communication and atypical patterns of activities and behaviors. The frequency of ASD is almost 4.5 times greater in boys than in girls [79]. The exact trigger of autism is unidentified. Up to 20% of ASD cases were linked to genetic alterations [80]. Other factors include immune dysfunction, inflammation, and embryonic exposure to anticonvulsant drugs [1]. Though the frequency of autism is growing, no medicine has been developed for the therapy of the ASD core symptoms [79].

Autism has been associated with disfunction of the endocannabinoid system [81, 82]. The ECS disorder was linked to the pathology of neurological disorders and to the behavioral deficits and neuroinflammation detected in autism [83, 84]. Pathophysiological processes generating the autistic neurobehavioral disfunction involve irregular synaptic plasticity and immune and metabolic disorders that are controlled by ECS [85]. The ECS plays a significant role in the development of the central nervous system (CNS) [17, 86]. In the CNS, CB1 receptors were found in the cerebellum, hippocampus, and the basal ganglia, which are zones of dysfunction in ASD [87, 88]. Autism was also correlated with dysregulation of the immune system [89, 90]. Localization of CB2 receptors in the immune cells, microglia and astrocytes has been associated with ASD-allied neuroinflammation [87, 91, 92, 93]. Raised autoimmune activity and increased levels of inflammatory cytokines and chemokines were correlated with microglial activation in ASD patients and were results of the pro-inflammatory status of the immune system [1, 18]. Alteration in monocyte and macrophage reactions, abnormal T helper cytokine and immunoglobulin levels, and decreased level of lymphocytes were detected in ASD children [1, 94]. Besides, elevated level of pro-inflammatory cytokines was linked to regressive forms of autism and typical behavior deficits [18].

4.1 Changes in the endocannabinoid system in autism

Research confirmed involvement of the ECS in ASD [1]. The endocannabinoid system impacts neuromodulation, emotional responses, behavioral reactivity, and social interaction [1, 95]. Disorder of the ECS might damage social play and reciprocity [95]. Dropped CB1 expressions were discovered in the brains of ASD individuals [18]. Motivation of the CB1 directly by agonist WIN55212-2 or indirectly by 2-AG inhibitor has increased the spatial memory in laboratory animals [96]. Polymorphism in CNR1 gene, encoding the CB1 receptor was related to modulation of striatal responses and gaze duration to social reward [97, 98], suggesting that altered affinity to the CB1 receptors could produce deficits in social rewards detected in autism. Animal studies have shown social play increases AEA concentrations in some brain regions [82]. Elevated AEA levels created the CB1 activation and improved social play [99], advising social play behavior deficit might be produced by low AEA levels in critical brain zones. Conversely, it was reported that excitement of CB1 receptors inhibited the typical excitation of complex social actions by affecting cognitive functions [99, 100]. Furthermore, a downregulation of alternative receptors involved in social play behaviors, GPR55 and PPAR, was displayed in animal model of autism [95]. The behavioral alterations could be facilitated by activation of PPARγs by endogenous agonists, OEA or PEA, as stimulation of hippocampal PPARγ improves cognitive performance [101]. PEA’s intestinal anti-inflammatory property is important since a portion of autistic inflammatory disorder is produced by gastrointestinal immune system [1]. The anti-inflammatory impact of PEA is utilized by stimulation CB2, GPR55, and PPARγ receptors [102].

Alteration of the ECS influences ASD-associated social and cognitive impairments in animal genetic models. CB1 density in the hippocampus of mice with autism-like phenotype (BTBR mice) was increased by 15–20%. Interaction of CB1 agonist CP55940 to Gi/o-coupled receptors in the BTBR models was also higher, demonstrating increased sensitivity [103, 104]. In the same animals enhanced AEA activity at CB1 targets improved social deficiency and decreased locomotive function [105]. The therapy of BTBR mice with the FAAH inhibitor, URB597, and THC improved the social behavior deficit [105, 106]. The BTBR models have also upregulated mRNA CB2 levels and elevated CB2 expression in their brain [106, 107]. A clinical investigation displayed upregulation of CB2 gene expression in peripheral blood mononuclear cells in ASD patients [108], which might be a compensatory mechanism of the autism-associated inflammation [1]. The augmentation of CB2 could be negative response to decrease the proinflammatory reactions since AEA suppresses the release of proinflammatory cytokines through CB2-mediated mechanism. In the FXS autistic animal model, URB597 enhanced AEA activity, improved memory, and anxiety-like behavior, and inverted the social impairment [109]. In Shank3B−/− mice ZL184 (MAGL inhibitor) produced an increase of 2-AG levels and improved social interaction deficits [110]. Alteration in neuroligin-3, 4 gene, NLGN 3,4 was correlated with intelligent debility, seizures, and ASD behavior [111]. Findings in genetic animal models with a neuroligin-3 substitution and a neuroligin-3 deletion showed neuroligin-3 is essential for EC signaling [112]. A study has reported WIN55212-2 might decrease aggressive behavior of neuroligin-3 R451C mouse model of autism via modification of CB1 receptor [113]. Another animal model, VPA model has alterations in ECS and corresponding ASD-like anomalies [95, 114]. Decreased expressions of mRNA PPARα and GPR55 in hippocampus and cortex, reduced amounts of FAAH and unusual AEA activity facilitate autistic behaviors in VPA animals [95, 114]. In the VPA rats the FAAH inhibitor PF3845 increased AEA signaling and impaired the difference in social behavior [95]. Another FAAH inhibitor, URB597 improved social conditions, repetitive and emotional behaviors in VPA animals [18]. Raised 2-AG levels have corrected behavior weaknesses in VPA rats [115]. The reduced endocannabinoid and enzymes levels and upregulation of CB receptors lead to lowered endocannabinoid signaling and link alterations in the ECS with ASD. Based on this finding, the ECS can be recommended as a novel target for ASD therapy.

4.2 Cannabinoids as a potential therapy of ASD

Cannabis and cannabinoids have been shown to be efficient as a therapy for some neurological disorders including ASD. In animal ASD models, CBD inversed the behavioral disorders by increasing AEA plasma concentrations and strengthening AEA signaling [116, 117]. In C57BL/6 J mice, CBD diminished marble-burying behavior that is similar to repetitive and compulsive behaviors in ASD [18]. Moreover, CBD weakened autism-like social behavior and cognitive disorders in animal models of Dravet syndrome and schizophrenia [118, 119, 120].

Phytocannabinoid CBDV can also produce anti-autistic effects. A clinical study showed CBDV corrected atypical striatal circuitry toward neurotypical function in ASD patients [121]. In genetic Mecp2 animal model, CBDV improved AEA and OEA levels and decreased DAGL and CB1 and CB2 receptor expressions [1, 122, 123]. The compromised general health, behavioral disorders, memory deficits, sociability, and brain weight were repaired [122, 123]. CBDV also restored neurotrophic factor level and ribosomal protein phosphorylation, which are damaged in autism [123]. In VPA animals, cannabidivarin produced hippocampal microglia activation, rebuilt endocannabinoid signaling and reduced neuroinflammation [124]. Outcomes of the CBDV administration were repaired social deficiencies, memory shortages, repetitive behaviors and hyperlocomotion [124]. THC also has a therapeutic impact on autism. THC administration improved locomotor behavior and depressogenic aspect in animals with an autism-like phenotype [106]. Other studies have confirmed the association between behavioral disorders and alteration of the ECS as well as the ability of some cannabinoids to treat autistic symptoms, providing more support for the cannabinoids as an ASD therapy [1].

Cannabis usage as an ASD therapy gained a rising attraction in public media. Anecdotal cases demonstrated autistic children failing conventional treatment have responded to cannabis therapy. Parents of the children noticed significant symptoms lessening. An ASD boy spoke his first words after taking cannabis oil and then obtained substantial talking ability [1]. In a 10-year-old boy with ASD the FDA-approved drugs created life-threatening toxicities. He was started on cannabis and in 6 years the child was sociable and successful [1]. Other autistic children have also shown remarkable improvement in communications after treatment with cannabis [1].

There are lacking clinical data on the effect of cannabis on ASD. Numerous studies demonstrated cannabis is safe and successful in decreasing disruptive behaviors and improving social communication. In a single-case-study, dronabinol (THC) has reduced hyperactivity, irritability, stereotyped behaviors, and improved speech in a boy with autism [125]. Another study has reported that dronabinol alleviated self-injurious behavior of mentally retarded adolescents [126].

Optimistic outcomes in ASD patients treated with cannabinoids and raising anecdotal commentaries of cannabis positive effects directed to more scientific assessment. A clinical trial was initiated to assess the safety and efficacy of cannabinoids (CBD:THC, 20:1) in 150 ASD children [127]. This cannabinoid treatment caused a reduction of disrupting behavior. Another effect was a reduction in body weight in obese patients. This is important since antipsychotics accompany significant weight gain. No substantial adverse events were shown [127]. Although this study displayed cannabis might correct ASD disrupting behaviors, efficiency data were lacking. An additional investigation was suggested.

A recent clinical trial assessed the effect of cannabis extract intense in CBD in 60 children with autism. Significant improvements were found for social interaction, anxiety, psychomotor agitation, and concentration. Only three children in the treatment group had mild adverse effects [128]. In another investigation, cannabis oil containing CBD and THC (20:1) was administered to 188 autistic patients. Significant improvements were noticed in 30.1%, moderate in 53.7%, minor in 6.4% and no adjustment in 8.6% of the patients [129]. Same cannabinoids concentrations were used in a study with 53 ASD patients [130]. Self-injury, rage attacks, hyperactivity, and sleep troubles were bettered in most of these patients [130]. In 110 children and teenagers with autism CBD-rich cannabis generated a significant improvement in social communication [131]. ASD patients treated with CBD/THC mixture (75:1) showed improvement of core ASD symptoms. Adverse outcomes were mild and infrequent [132].

Overall, cannabinoids were found to be successful in relieving ASD symptoms. The cannabinoid therapy was associated with low incidents of adverse events and reductions in concomitant medications. However, it is essential to conduct more large-scale and long-term clinical trials to support these conclusions.

5. Epilepsy

Epilepsy is neurological illness that causes seizures or unusual sensations and behaviors. One third of the patients diagnosed with epilepsy are children. Epilepsy can affect children of all races and ethnic backgrounds and might have different reasons, although most of the cases have idiopathic origin [133]. Genetic alterations and brain damage as well as some illnesses may trigger epilepsy [133]. Treatment of pediatric epilepsy is challenging and includes pharmacologic, non-pharmacologic, and surgical options [134]. Unfortunately, childhood epilepsies are generally coupled with therapy-resistant seizures. Such severe seizures might produce long-term defects in perception, behaviors, and some other activities [135]. Resistance to epilepsy regimens has created real challenge in treatment of Dravet, Lennox-Gastaut, Doose, and West syndromes [136].

Dravet syndrome (DS) is a severe and pharmaco-resistant type of epilepsy. Certain anti-epileptic drugs (AED) can even aggravate seizures and should be avoided in patients with Dravet syndrome. Infants being treated for status epilepticus with phenobarbital developed cerebral atrophy with dramatic neurological worsening [137].

Lennox-Gastaut syndrome (LGS) is a severe, chronic, epileptic encephalopathy, primarily with childhood onset [138]. LGS syndrome begins in childhood, worsens during latency, and persists frequently into adulthood. The syndrome is refractory to anti-epileptic medications. Most patients develop moderate intellectual disability within a few years of onset of the syndrome [139].

Doose syndrome (DS) or Myoclonic-Astatic Epilepsy (MAE) is an uncommon childhood epilepsy with frequent myoclonic and myoclonic-atonic seizures. Children with MAE may also have other types of seizures. MAE outcomes depend on seizures severity and may vary from normal or severe developmental and learning delays [140].

West syndrome (WS) is a rare epileptic disorder happening in infants and characterized by infantile spasms, hypsarrhythmia, and developmental regression [141]. Neurodevelopment is normal in only 10–15% of affected patients [142]. Pharmacologic agents used to treat WS are not always effective.

Pediatric epilepsies are generally linked to treatment-resistant seizures. Management of these disorders needs more efficient treatment to prevent development-related neurological conditions.

5.1 Cannabinoid’s effect on epilepsy molecular targets and syndromes

Medical cannabis has created a significant research interest as a potential therapy option in epilepsy treatment. Studies investigated the effects of cannabinoids on molecular targets in animal models of seizure and epilepsy. The results of these studies are summarized in Table 1 [143].

Cannabinoid	Molecular target(s)
D9-Tetrahydrocannabinol (THC)	CB1R, CB2R, TRPV1, TRPV2
D9-Tetrahydrocannabivarin (THCV)	CB1, CB2, TRPV1, TRPV3, TRPV4
Cannabidiol (CBD)	GPR55, TRPV1, TRPV2, TRPV3, TRPA1, FAAH, TRPM8
Cannabidivarin (CBDV)	TRPV4, DAGLa
Cannabinol (CBN)	CB1R, TRPV4, TRPA1

Table 1.

Cannabinoid’s molecular targets studied in animal models of seizure.

The data demonstrated mixed efficacy in various acute seizure animal models [143]. CBD exerts its antiepileptic effects through several different mechanisms. Main molecular target responsible for the antiepileptic effect of CBD is still unclear. Some authors reported the role of the cannabinoid CB1 receptor in modulating seizure activity [144]. Other investigations indicated that cannabinoids produce anticonvulsant effects via non-CB1/CB2 mechanisms [145]. At low micromolar concentrations, CBD worked as a blocker of ENT and TRPM8 channels. Conversely, CBD enhanced the activity of 5-HT1a receptor, a3 and a1 glycine receptors, and TRPA1 channel [12, 146]. At higher micromolar concentrations, CBD activated the nuclear TRPV1 and TRPV2 channels and inhibited cellular uptake and degradation of AE [12, 147]. Additionally, CBD has a good affinity toward GPR55, which is involved in the modulation of synaptic transmission. CBD agonist action may weaken the synaptic transmission and produce antiepileptic effects [118]. Cannabinoids THCV and CBDV also produce anticonvulsant effects, most probably not via CB1 or CB2 pathways [34]. Similar to CBD, THCV and CBDV have an affinity to TRPV1, 2, TRPA1, and TRPM8, but processes of the relations are not identified. Cannabinoids have been demonstrated to be beneficial in experimental models of several neurologic disorders, including seizure and epilepsy (Table 2).

Cannabinoid	Model	Efficacy
D9-Tetrahydrocannabinol (THC)	Generalized seizure	Y
	Temporal lobe epilepsy	Y
Synthetic CB1R agonists (e.g., WIN55-212)	Generalized seizure	Y
	Partial seizure with secondary generalization	Y
	Temporal lobe epilepsy	Y
	Absence epilepsy	Mixed effect
Synthetic CB1R antagonists (e.g., SR141716A)	Generalized seizure	Na
	Absence epilepsy	N
	Partial seizures with secondary generalization	Na
	Epileptogenesis	Y
D9-Tetrahydrocannabivarin (THCV)	Generalized seizure	Y
Cannabidiol (CBD)	Generalized seizure	Y
	Temporal lobe convulsions/status epilepticus	Y
	Partial seizures with secondary generalization	Y
Cannabidivarin (CBDV)	Generalized seizure	Y
	Temporal lobe convulsions/status epilepticus	Y
	Partial seizures with secondary generalization	Y
Cannabinol (CBN)	Generalized seizure	Y

Table 2.

Cannabinoid efficacy in animal models of seizure and epilepsy [143].

^a

Indicates a proconvulsant effect.

CBD has been shown to have anticonvulsant effect in different animal seizure prototypes [148, 149]. In pilocarpine animals, CBD radically lowered fraction of rodents with very intense seizures. In the penicillin animals, CBD substantially reduced the intensity of seizures, corresponding mortality, and number of rodents with critical tonic-clonic seizures. Besides, CBD decreased seizure intensity and number of death cases in generalized seizure model [149, 150]. CBD caused concentration-related and region-dependent attenuation of chemically induced epileptiform activity in hippocampal brain slices [150]. Other cannabinoids, THCV and CBDV were also effective in lessening seizures and generated anticonvulsant effects in animal models of epilepsy [34].

Unfortunately, seizures remain refractory to pharmacological treatments in a substantial portion of pediatric patients. After unsuccessful antiepileptic treatment, parents initiated epilepsy therapy with cannabis containing products. More than 84% of the parents noted a reduction in the frequency of seizures and 11% reported that their children became seizure-free [151]. The parents highlighted some of the additional beneficial outcomes such as better sleep patterns, increased alertness, and an overall positive change in mood [151].

Several randomized, double-blind, placebo-controlled studies evaluated the activity of a new anti-epileptic formulation of purified CBD. Studies have shown that CBD was beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy [152, 153]. In open label study in patients with drug-resistant seizures, CBD given as add-on therapy reduced seizure frequency [153]. CBD also greatly diminished convulsive-seizure rate in DS patients [153]. CBD was very well tolerated and did not produce psychotic symptoms even at high doses. As a result, the first CBD drug (Epidiolex) was authorized in 2018 as a therapy for LGS-, DS-, and tuberous sclerosis complex (TCS) -associated seizures [154]. This approval ensured the safety and effectiveness of CBD in seizure disorders.

THC also helps in reducing epileptic seizures. In animal seizure models THC, AEA, and WIN55212-2 exhibited potent anticonvulsant effects via CB1 activation [155, 156]. A clinical study reported that THC (Dronabinol, Marinol) reduced spasticity, improved dystonia, increased interest in the surrounding, and produced anticonvulsive action [70]. However, the results of THC experiments are inconsistent. Some studies informed THC did not exhibit any value as a seizure therapy. Other investigations demonstrated that THC even potentiates convulsions and provokes the epileptiform activity [157]. Recent study reported that administration of THC-like substances calmed seizures but leaded to post-seizure oxygen deprivation in the brain [158].

6. Additional effects of cannabinoids in neurological disorders

6.1 Neuroprotection

Cannabinoids have demonstrated neuroprotective, immunomodulatory, anxiolytic, and antidepressant benefits. Cannabis and related compounds exhibit the neuroprotection mostly because of their ant-inflammatory, the anti-oxidative, and the anti-excitotoxicity properties. Both THC and CBD provide neuroprotection against the in vivo and in vitro toxicity of 6-hydroxydopamine (6-OHDA) [159]. In a study, CBD regained 6-OHDA-made dopamine drop and reduced oxidative stress [8]. CBD also lessened a rise in NADPH-oxidase levels and reduced indicators of oxidation, inflammation, as well as cell mortality [160]. The mechanism by which CBD reduces NADPH oxidase expression and inhibits oxidative injury suggests a straightforward association involving CB1 and mitochondrial brain activity [161]. Cannabinoid’s phenolic ring plays an important role in an anti-oxidative action versus glutamate-persuaded neurotoxicity [162]. Moreover, CBD greatly diminished oxidative destruction produced by hydroperoxide and was more defensive to glutamate-associated neurotoxicity than alpha-tocopherol [163]. These findings support the hypothesis that the treatment with cannabinoids having antioxidant effects may modulate mitochondrial reactive oxygen production.

Several studies showed that cannabinoids have anti-inflammatory properties and may attenuate neuroinflammation and produce beneficial effects in acute inflammation and chronic neuropathic states [143]. Inflammation has been shown to be a crucial pathological factor responsible for the death of dopaminergic neurons [164, 165]. Individuals with neurodisorders have elevated expression of active microglia suggesting deep involvement of the glial chambers in neuroinflammation [166]. Cannabinoids overcome stimulation of microglia and cytokine production and as a result, reduce the inflammation [167, 168]. Cannabinoids also activate the CB2 receptor, which mediates the anti-inflammatory effect and preserve cells from excessive apoptosis [34, 169]. Moreover, a recent study reported that CBD stimulates neurogenesis [170]. In contrast, THC produces its anti-inflammation impact by CB1 stimulation [171, 172]. Cannabis/cannabinoids also produce anti-inflammatory influence via reduction of blood vessels constriction and repair blood stream to the affected zones [173]. Based on the information, it is possible to conclude cannabinoids are hypothetically valuable as neuroinflammation therapy.

Moreover, cannabis might deter brain injury via protection against neural damage. Cannabinoid’s protective processes involve CB2 stimulation and regulation of neuronal homeostasis [174]. Activation of CB1 receptors is another mechanism of neuroprotection. Cannabinoids activating the CB1 receptor are anti-excitotoxic due to suppression of glutamatergic activity with a subsequent decrease in nitric oxide creation [175, 176]. The mixture of THC and CBD exhibited neuroprotection impact interacting with CB1 and CB2 [177]. Additionally, THC lowered tyrosine hydroxylase-positive neurons death and demonstrated neuroprotection result via PPAR𝛾 stimulation [34, 178]. Cannabis/cannabinoids have potential to suspend/block ongoing brain dopaminergic deterioration and have neuroprotective value in management of neurodegeneration.

6.2 Analgesic effect of cannabinoids

Pain is a significant and often underestimated symptom of neurological disorders. Medications to treat pain include analgesics, opioids, and, in some cases, antiseizures. Unfortunately, the drugs do not have comprehensive effectiveness and can produce substantial adverse effects. Cannabis has pain-dismissing value. It was reported that CB receptors in CNS have ability to modify pain sensitivity [179]. In medical investigations Sativex and smoked cannabis greatly decreased pain feeling in neuropathic patients [180, 181, 182]. In another study, cannabis substantially demoted pain in patients with distal symmetrical polyneuropathic disorder [183]. Additional studies reinforced that cannabis-based medicine significantly decreases chronic pain intensity in patients with neurological disorders [8]. These findings are supporting the efficacy of cannabis in relieving pain in various disease states including neurological disorders.

6.3 Antidepressant effect of cannabinoids

Depression and mood disorders are the common symptoms of neurological disorders. Therapy of co-occurring depression and mood conditions is complex and standard pharmacotherapy may be ineffective. It was reported that mood and emotional activities are under control of the endocannabinoid system and deficit or obstruction of the EC signaling system may produce depressing signs [184]. For instance, rimonabant, CB1 antagonist promoted anxiety and depression [8]. Moreover, CB1 gene mutations were linked to depression in PD patients [185]. In genetic animals, THC has stimulated CB1, intensified serotonergic action, and generated antidepressant effect [186]. Other investigations showed AEA hydrolysis blockage produces antidepressive impact due to enhanced serotogenic and norepinephric neuronic action [187].

Cannabinoids have possibility to lower depression and mood conditions indicators. CBD shows antidepressive and antipsychotic impacts in depression, and some other mental conditions [1]. THC in mixture with CBD also produces neuroleptic effect [188]. But consumption of cannabis herb produced controversial outcomes on depression and mood disorders [189]. Some studies reported anxiety and increased symptoms of depression. Conversely, many cannabis users describe an improvement in mood [190]. Understanding long-term consequences of cannabis use is important in managing neurological conditions, especially in pediatric patients. The advances of cannabis should be evaluated versus the dangers/harmful outcomes.

6.4 Antianxiety effect of cannabinoids

Many patients with neurological disorders have anxiety. The current anxiety treatment is cognitive-behavioral therapy together with antianxiety medicines. Administration of these drugs lead to dependence and tolerance with increasingly larger doses needed and produces many overdose-related fatalities. Cannabinoids impact on anxiety is complicated since cannabinoids antagonistically influence brain functions [1]. THC psychotropic stimulation is transient and could create retention and intellectual destruction [191]. THC was also linked to psychosis and severe anxiety [192]. Oppositely, CBD generates anxiolytic impact and blocks THC anxiogenic/psychotogenic influence [193]. CBD increases AEA concentrations via inhibition of FAAH [1]. Elevated AEA concentrations are associated with lowered depression and nervousness. Additionally, CBD anti-anxiogenic impact might be due to modulation of serotonin, adenosine, TRPV1, GABAA and PPAR receptors [1]. CBD exhibited effectiveness as anxiolytic agent in genetic animals [194, 195]. Animal studies advocate CBD has value as a prospective medicine for various anxiety disorders and as an inhibitor of lifelong anxiogenic outcomes [196, 197]. Medical research proves results of animal studies. CBD radically weakened anxiety, intellectual and speaking failings and improved remembrances in patients with common anxiety syndromes [1]. Brain examinations demonstrated alteration of blood circulation in limbic brain regions after CBD administration. This finding was associated with CBD anti-anxiety effect [198]. In another study, CBD as add-on treatment reduced anxiety in 79.2% patients. However, 15.3% of the patients faced intensified anxiety [199]. Some additional investigations have also informed that CBD produces anxiolytic effect in various populations [1]. Nonetheless, extra studies are needed to confirm the value of CBD as a therapy for anxiety.

6.5 Effect of cannabinoids on sleep disorders

Various sleep problems are the very frequent syndromes in neurological disorders [200]. Pharmacologic treatment of sleep conditions involves drugs most of which are hypnotic. These medications are a source of severe adverse effects. Cannabis has demonstrated slight calming validity in animals and humans [201]. A medical study revealed that cannabis administration bettered sleep quality and decreased sleep length in 79% individuals [202]. Nabiximols improved subjective sleep factors in 2000 patients with pain [203]. THC and CBD affect sleep differently. In an early clinical research, THC generated sleepy result [1]. Conversely, in a later study THC did not create an impact on nighttime sleep and enhanced daytime sleep [204]. Another trial reported that THC reduced nocturnal sleep length due to developed tolerance to its sedative impact [205]. CBD opposes THC action via activation of the brain awaken-related areas and increasing dopamine concentrations [1]. CBD augmented sleeplessness throughout light-on time, improved lights-off sleep, and inhibited sleep rebound after sleep absence [1]. In study with 72 individuals CBD improved sleep results in 66.7% of the patients [199]. CBD appears to optimize sleep and improve associated sleep problems and may have a beneficial value in some sleep conditions.

7. Summary

Cannabis and related compounds have recently been studied as promising therapeutic agents in treatment of neurological disorders. Research studies have provided evidence for the potential effectiveness of medical marijuana and its components in the treatment of these disorders. Cannabis may offer a viable alternative or addition to the current treatment of neurological diseases. However, cannabis and related compounds may create not only the medicinal consequences but also generate threatening conditions. Constant cannabis consumption was correlated with several mental difficulties. Additional worries are relative absence of standardizations and regulations, inaccurate dosage, and potential adverse results. More investigations are required to obtain additional information on medicinal value and safety of cannabinoids.