Abstract
Cannabinoids, either phytocannabinoids or synthetic derivatives of medical cannabis, exhibit a variety of potential pharmacotherapeutic effects by acting on the endocannabinoid system, through interactions with the cannabinoid receptors (CB1, CB2, and other receptors). Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes spasticity, neuropathic pain, urinary bladder dysfunction, and sleep disturbance. Treatment with cannabinoids decreases the severity of disease in animal models of experimental autoimmune-Theiler's virus-induced-encephalomyelis or toxic demyelination. CBD anti-inflammatory effects decrease CNS inflammatory infiltrates, microglial activation, and cytokines IFN-γ, IL-Iβ, IL-17, or TNF-α, whereas Δ9-THC reduces spasticity. Add-on treatment with cannabinoids (Nabiximols, Sativex, equimolar concentration of THC:CBD) have demonstrated potential in alleviating the symptoms of patients with MS. This chapter reviews the evidence-based therapeutic effects of cannabinoids and their mechanisms of action relevant to MS.
TopIntroduction
Multiple Sclerosis
Multiple Sclerosis (MS) is an immune-mediated demyelinating disease in which the immune system attacks the myelin sheath and damages the central nervous system (CNS), forming MS lesions, plaque, or scars. MS lesions can occur anywhere in the CNS, including the spinal cord, gray matter, optic nerves, and periventricular areas (Hagemeier et al., 2012). The demyelination damages the motor nerve fibers and causes inflammation, metabolic imbalance, and severe impairment of nerve signal transmission between the brain and spinal cord as a result of irreversible axonal degeneration (Alizadeh et al., 2015). Neurological symptoms usually develop following conduction blockage within the fibers. Such pathogenesis causes heterogenic symptoms, including spasticity, muscle spasms, oculomotor abnormalities, optic neuritis, tremors, neuropathic pain, diplopia, neurogenic bladder, gait problems, paresthesia, and cognitive dysfunction (Allegri et al., 2011). Spasticity and neuropathic pain are frequent symptoms of MS that reduce the quality of life of MS patients. Spasticity causes the stiffness of the muscles (or contracture), muscle spasms, and nociceptive pain. Spasticity, a form of elevated muscular tone, is a common (affecting 60-84%) and severe MS symptom that worsens with disease progression. Contractures in muscles, tendons, and joints, which can worsen limb posture, mobility, and function, may evolve as adaptive traits (Hugos & Cameron, 2019). Lesions of the somatosensory system slow down spinal somatosensory conduction, causing balance deficits and neuropathic pain. During the course of the disease and the broad clinical spectrum, the signs and symptoms of MS are unpredictable and highly variable. A French neurologist, Jean-Martin Charcot, was the first to characterize MS as a distinct nosological entity (Joy & Johnston Jr., 2001). Described as la sclérose en plaques in 1868, Charcot uses the anatomopathological and clinicopathological features of presentation in person to diagnose MS having disseminated grayish and reddish patches of varying sizes in both the brain and spinal cord. In MS, irreversible axonal and myelin loss is related to clinical impairment.
Disease Course and Diseases Burden of MS
Relapsing-remitting multiple sclerosis (RRMS), which causes flare-ups of inflammatory demyelination in the CNS along with an acute worsening of neurological activities and existing symptoms, affects patients in the majority of MS cases (roughly 85 percent) (Goldenberg, 2012). RRMS could be either active (showing evidence of new relapses), non-active (no disease activity), worsening (increased disability), or stable (no increasing disability). During relapsing MS, the axonal loss is frequent (Cree et al., 2021). The edema associated with new MS lesions is a major factor in neurological relapses because it blocks conduction potentials. Nearly 60–70% of RRMS patients progress to SPMS within 20–25 years, which is characterized by progressive neurological impairment after an initial relapsing–remitting course (Barzegar et al., 2021). Furthermore, ~10% of MS have a disease course that includes a persistent deterioration in neurological function without recovery, which is categorized as progressive relapsing MS (PRMS) (Dutta & Trapp, 2014). MS is a burdensome, chronic inflammatory and autoimmune disease, which has complex etiology. Young adults are frequently affected by non-traumatic neurological disabilities, with MS being the most common cause, predominantly in females, with a usual diagnosis at approximately 30 years (Beyers, 2020). Based on the Atlas of MS International Federation, the global mean prevalence rate of MS is estimated at 2.8 million MS cases, which corresponds to a 35.9 per 100,000-population increase from 33 cases per 100,000 population (Walton et al., 2020). In the countries with better socioeconomic positions, MS has a higher prevalence. The United States has the highest number of MS cases (913,925) but Germany has the highest prevalence about 303 per 100,000 population (Dilokthornsakul et al., 2016). Therefore, MS leads to remarkable socioeconomic impacts and also affects the quality of life of patients and their care-takers (Scalfari et al., 2013).
Key Terms in this Chapter
?9-tetrahydrocannabinol (THC): A principal psychoactive constituent of cannabis.
Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease (TMEV-IDD): an animal model of virally induced inflammatory demyelination.
Experimental Autoimmune Encephalomyelitis (EAE): A widely accepted animal model of inflammatory demyelinating diseases, such as multiple sclerosis (MS), designed for research on the neuroimmune response following exposure to CNS-restricted myelin antigens.
Neuropathic Pain: Damage or injury caused by a lesion or disease of the somatosensory system, including peripheral fibers and central neurons, to the nerves that transmit impulses from the skin, muscles, and other regions of the body to the brain and spinal cord.
Spasticity: An abnormal increase in muscle tone or stiffness of muscle that impairs speech, movement, or may cause discomfort or pain.
Anandamide (AEA): A lipid mediator that binds to CB1 receptors that mediates pharmacological actions of ? 9 -tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa .
Cannabidiol (CBD): A non-intoxicating, phytocannabinoid found in the Cannabis sativa plant, also known as cannabis or hemp.