2. Cannabinoids and the Endocannabinoid System (ECS)
2.1. Cannabinoids
Cannabis sativa,
Cannabis indica, and
Cannabis ruderalis are the three most common species of the cannabis plant, which is in the Cannabaceae family
[32][5]. The cannabis plant has a long history of practical uses, including as a food and oil source and even in producing paper and linen, two of man’s necessities
[33][6]. In addition, its psychoactive qualities enabled its use in medical surgeries, even though its components and mechanism of action in the human body were unknown at the time
[34][7]. Phytocannabinoids, endocannabinoids, and synthetic cannabinoids are the three primary sources of more than sixty cannabinoids with physiological effects
[8]. The cannabis plant contains more than 100 phytocannabinoids, including the two most significant ones, which are Δ
9-tetrahydrocannabinol (THC) and cannabidiol (CBD). It is believed that Δ
9-THC is the primary psychoactive compound found in cannabis
[9].
2.2. The Endocannabinoid System (ECS)
The primary impact of cannabinoids occurs through the endocannabinoid system (ECS), which consists of a set of signaling pathways regulated by cannabinoid receptors cannabinoid-1 (CB1) and cannabinoid-2 (CB2). The activation of these pathways is commonly triggered by the attachment of endogenous cannabinoids (endocannabinoids) like Anandamide (AEA) and 2-Arachidonoyl Glycerol (2-AG) to the CB1 and CB2 receptors
[35][10]. The CB1 receptors are situated primarily in nerve terminals and function to inhibit the release of neurotransmitters. Conversely, CB2 receptors are predominantly located in immune cells. Their role encompasses regulating cytokine production and migrating immune cells within and beyond the central nervous system
[36,37][11][12]. The endocannabinoid system (ECS) is essential for maintaining the body’s homeostasis by regulating the balance between the inhibitory and excitatory states of the nerves. This is accomplished by activating CB1 receptors located on inhibitory GABAergic and excitatory glutamatergic presynaptic terminals, inhibiting neurotransmitter release
[38][13]. Additionally, the ECS is responsible for many physiological and pathological processes in the body. It controls biological mechanisms, such as pain, food intake, anxiety, and memory
[39][14].
3. Neuroprotection Effect of Cannabinoids
The neuroprotective effect of cannabinoids in multiple sclerosis (MS) may be attributed to their role in regulating the excessive excitability of neurons in the central nervous system (CNS). The CB1 receptor is located predominantly in GABAergic neurons within the hippocampus. It is also found in neurons that use glutamate as a neurotransmitter and in astrocytes and subcellular compartments
[40,41][15][16]. The release of cholinergic and dopaminergic neurotransmitters is regulated by cannabinoid signaling and the regulation of excitatory/inhibitory transmission by CB1 receptors, as shown in
Figure 1 [42,43][17][18]. Studies have shown that cannabinoid-based therapy can effectively reduce symptoms of multiple sclerosis, such as spasticity, pain, gallbladder dysfunction, and tremors
[44][19], which is achieved by increasing the secretion of endocannabinoids in targeted areas, activating CB1 receptors, and limiting the release of neurotransmitters from presynaptic terminals, which results in a reduction in the excessive excitatory state in the neurons and a potential neuroprotection effect of the CNS
[45][20]. In addition, cannabinoids’ impact on the regulation and modulation of microglial cells within the CNS has been investigated. Inflammation has been shown to elevate CB2 receptors in glial and immune cells, even though they are less prevalent in the healthy brain, as observed in EAE models
[46][21].
Figure 1. Diagram depicting the biological effects of cannabis’ active ingredients on multiple sclerosis. Abbreviations for cannabinoid receptors 1 and 2, tetrahydrocannabinol, and cannabidiol created with Biorender.
Moreover, blood samples from MS patients exhibited higher levels of pro-inflammatory cytokines and excessive expression of CB1 and CB2 receptors
[47][22]. These findings, along with the observation that activating CB2 receptors reduces the secretion of TNF-α and oxidative free radicals within the brain, underscore the critical role of the ECS signaling pathway and cannabinoids in controlling CNS inflammation through immuno-regulatory functions in neurons. Furthermore, this plays a vital role in the neuroprotection of the CNS by mitigating oxidative stress. Interestingly, the part of cannabinoids in neuroprotection could also be due to their antioxidant effect. Preliminary factors in neurodegenerative diseases include oxidative stress, which occurs when reactive oxygen or nitrogen species surpass antioxidants. CBD, being a phenolic compound, exhibits reactive oxygen-scavenging properties. In experimental studies on PC12 cells, CBD demonstrated approximately 50% higher antioxidant activity than vitamins. It effectively reduced oxidative stress caused by reactive oxygen species (ROS) by limiting lipid peroxidation and inhibiting the accumulation of ROS products. Additionally, CBD reduced induced cell-apoptosis factors, such as DNA fragmentation and caspase-3 activation. These findings highlight the potential neuroprotective effects of CBD against oxidative damage in neurodegenerative conditions
[48][23].
4. Immunomodulatory Effect of Cannabinoids
The presence of cannabinoid receptor 2 (CB2) in white blood cells has sparked interest in the ability of cannabinoids to regulate the immune system. THC binds to CB1 receptors in the brain, whereas CB2 receptors are found predominantly in immune cells in the peripheral nervous system. The precise role of the endocannabinoid system in immune regulation is not yet fully comprehended, despite evidence of cannabinoids affecting immune cell function
[49,50][24][25]. According to a study by Nichols et al. in 2020, cannabidiol (CBD) has been recognized as an anti-inflammatory substance and has some characteristics of suppressing the immune system
[51][26]. Exposure to high concentrations of cannabis can impair immune responses, according to in vitro and in vivo research. This reduces the activity and cytokine production capacity of macrophages, natural killer cells, and T lymphocytes
[52][27]. However, rather than reducing immune system activity, an adequate amount of cannabis in the body increases lymphocyte metabolic activity and boosts the production of pro-inflammatory cytokines
[53][28]. These dose-dependent cannabinoid activities point to the biphasic effect of cannabis constituents
[52][27]. Despite this potential biphasic effect of cannabinoids, CBD has been shown in several studies to act as an immunomodulator during inflammation, regulating the inflammatory response by influencing various inflammatory cascades involving both anti-inflammatory and pro-inflammatory mediators, as discussed in the study by Furgiuele et al.
[54][29]. Inflammation, axonal demyelination, and symptoms like spasticity and pain are all helped by these neuroprotective mechanisms. Using EAE murine models of multiple sclerosis, researchers found that CBD, with the help of myeloid-derived suppressor cells (MDSCs), improved EAE progression dose-dependently. According to the research conducted by Elliott et al., CBD had several effects, including a decrease in T-cell proliferation in the central nervous system (CNS) and a decrease in the pro-inflammatory cytokines IL-17 and IFNγ
[55][30]. Additionally, CBD treatment decreased inflammation and axonal loss in multiple sclerosis models engineered with myelin oligodendrocyte glycoprotein (MOG) to imitate EAE. The reason for this was that CBD inhibits the infiltration of T-cells and the activation of microglial cells, as reported in the study by Kozela et al.
[56][31].
5. Therapeutic Potential of Cannabinoids
Cannabidiol has demonstrated encouraging effects in treating a range of medical conditions. Within the domain of epilepsy therapy, CBD has shown efficacy as an anticonvulsant medication, particularly in the treatment of severe childhood epilepsy syndromes such as Dravet syndrome and Lennox–Gastaut syndrome. Furthermore, CBD has been studied for its potential as an antidepressant, antipsychotic, and anxiolytic agent. Moreover, CBD has demonstrated an anticancer effect. While further research is necessary to comprehend its advantages fully, CBD exhibits promise as a reliable and efficient medication, indicating therapeutic implications for inflammation, neuroprotection, epilepsy, depression, and pain
[57,58][32][33]. These findings support the potential therapeutic benefits of cannabinoids in managing neuroinflammation and its impact on MS-related pathology. Research has investigated the potential of cannabinoids to inhibit the progression of multiple sclerosis (MS) and provide neuroprotection in animal models. The results have varied under different experimental conditions, as specified in
Table 1, and there have yet to be any human trials conducted with appropriate doses. CBD has demonstrated effectiveness in animal MS models and human cells tested in a laboratory setting. However, its impact on the immune system of MS patients is yet to be observed
[59][34]. Individual variance and genetic polymorphism may point to distinct processes or responses to cannabinoids, leading to a reasoned explanation.
Table 1.
Clinical studies on the use of cannabinoids for the management of multiple sclerosis.