Cannabis and Multiple Sclerosis-Related Symptoms: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

Multiple sclerosis (MS) is known as an autoimmune disease that damages the neurons in the central nervous system. MS is characterized by its most common symptoms of spasticity, muscle spasms, neuropathic pain, tremors, bladder dysfunction, dysarthria, and some intellectual problems, including memory disturbances. Several clinical studies have been conducted to investigate the effects of cannabis on the relief of these symptoms in MS patients.

  • Cannabis sativa
  • marijuana
  • cannabinoids
  • 9-tetrahydrocannabinol (THC)
  • multiple sclerosis (MS)

1. Introduction

MS is a neurological disease with an autoimmune origin that affects and damages the central nervous system and affects 2.3 million people worldwide [1][2]. This demyelinated disease leads to severe impairment of nerve signal transmission between the brain and spinal cord that causes a loss of myelin sheath [1][2].MS has been characterized by symptoms of spasticity, muscle spasms, tremors, bladder dysfunction, neuropathic pain, dysarthria, and some intellectual problems, including memory disturbances [3][4]. Some drugs have been licensed to slow down disease progression and reduce relapse frequency [3]. However, more studies are needed to further alleviate the disabling symptoms of MS patients.
In the 21st century, the Sativa plant has become the most widely used illicit drug [5]. It is also known as hemp, cannabis, or marijuana, and comes in a variety of forms, including cigarettes or hash pipes and sweets or brownies [5][6]. The cannabis plant, which includes over 560 identified components, is primarily composed of phytochemicals [5]. The two prominent species of Cannabis plant, which are mostly used for recreational and medical, are Cannabis indica and Cannabis sativa (C. Sativa) [7][8]. Both plants are composed of different cannabinoid compositions of THC and CBD [9][10]. Previous research has shown the different effects of each species due to the different concentrations of the two main components [11]. C. Sativa has a higher ratio of CBD to THC and the reverse is seen for C.indica [10]. There are about 100 cannabinoids in Cannabis sativa [12], the most well-known of which are 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (Figure 1a,b). The endogenous cannabinoid system, which includes CB1 and CB2 receptors, is where cannabinoids get their effects. The psychotropic effects of THC are primarily mediated by a CB1 receptor agonist actions. CBD, on the other hand, is hypothesized to bind to CB1 and CB2 receptors and act as an antagonist [5][13].
Figure 1. The molecular structures of (a) THC, (b) CBD, (c) Nabiximols, (d) Dronabinol, and (e) Nabilone are depicted in this diagram.
Cannabis has been used for over 5000 years, with the discovery of the endogenous cannabinoid system occurring more than a decade ago. CB1 and CB2 are cannabinoid receptors that are linked to adenylyl cyclase negatively and mitogen-activated protein kinase positively through the Gi/o protein [14][15]. CB1 and CB2 are distributed in the central and peripheral nervous systems and immune systems [16]. CB1 receptors are found mostly in nerve terminals in the central nervous system and some peripheral tissue and are linked to a specific type of calcium and potassium channel via a G protein. Because it blocks pain pathways in the brain and spinal cord, the CB1 receptor’s main function is to suppress neurotransmitter release, and it plays a crucial role in mediating the pain-relieving effect of cannabis [17].
Phytocannabinoids, endocannabinoids, and synthetic cannabinoids are the three types of cannabinoids. The major chemical components of cannabis are phytocannabinoids, which include a variety of non-cannabinoid C21 terpenes phenolic compounds, or C22 for the carboxylate group, which is largely synthesized in cannabis [18][19]. Heat can decarboxylate phytocannabinoids, which are biosynthesized in carboxylated form [20]. Cannabis is considered a promising anti-inflammatory and immunosuppressive agent due to its central and peripheral actions on CB1 and CB2 receptors that mediate different intracellular pathways when activated [21].In addition to the effects of the cannabinoids on CB1 and CB2 receptors, cannabinoids have effects on nuclear receptors and ion channels by their activity on other transmembrane G protein-coupled receptors (GPCRs) and have a modulating activity on opioid and serotonin receptors [16]. THC is a psychoactive component of cannabis with the highest potency. THC can be utilized to treat neuropathic and chronic pain because of its intoxicating, anti-emetic, and anti-inflammatory properties [22]. CBD does not cause psychosis, although it does have pharmacological effects on pain and spasticity [23].
The main psychoactive constituent of the C. Sativa plant, 9-THC, was discovered in the late 1980s and was shown to have activity on a specific cannabinoid receptor in the brain (the cannabinoid CB1 receptor), which had a huge impact on the development of cannabinoid therapeutic drugs and their potential to relieve MS spasticity symptoms [24]. Preclinical animal studies of MS suggested that cannabinoids have anti-septic effects due to the activation of CB1 receptors, which inhibit the release of classical neurotransmitters, such as glutamine, while also decreasing neuronal excitability by activating somatic and dendrite potassium channels [25][26].
CBD is a key non-psychotropic cannabinoid present in C. Sativa that accounts for up to 40% of the cannabis plant’s extract and binds to a wide range of physiological targets of the endocannabinoid system in the human body. CBD has shown potential in the treatment of MS symptoms. CBD, in particular, has been shown in numerous trials to reduce stiffness, discomfort, inflammation, exhaustion, and depression in MS patients, resulting in increased mobility [27][28]. CBD also affects the non-cannabinoids receptors GPCRs and ion channels that will lead to pain regulation and anti-inflammatory effects through receptor modulation [16].
Several attempts have been made to determine the primary genetic factor contributing to MS progression and severity [29][30][31]. Although it was demonstrated that genetic effects on MS disease severity and susceptibility are polygenic with modest influence [30][31], more studies are needed to further understand the pharmacogenetics of MS disease and to define the molecular target of CBD in MS patients by performing the ex vivo/in vitro research in human immune cells as reported by Furgiuele et al. [31].
The efficacy of oromucosal spray nabixiomol, oral dronabinol, and oral nabilone forms of cannabis on MS-related spasticity, pain, tremor, urine function, sleep disturbances, quality of life, disability, and disability progression is assessed in this review. The sections below go through the signs and symptoms of MS, as well as the treatment options.

1.1. MS-Related Symptoms

1.1.1. Spasticity in MS

Spasticity is a common symptom of MS, affecting 60–84% of patients, particularly throughout the disease’s progression [32]. Spasticity is caused by injury of the higher corticosteroids motor neurons, as well as aberrant supraspinal driving of spinal reflexes [33], which can exacerbate other MS symptoms and harm the patient’s quality of life [34][35][36].
MS spasticity is a complicated condition characterized by the most prevalent symptom, muscle rigidity, which is induced by the stretch reflex’s hyperexcitability. Fatigue, discomfort, and bladder dysfunction are among the more prevalent and troubling symptoms [37]. Combining nonpharmacological and pharmacological therapies is the most commonly employed treatment [38]. Increasing severity of MS spasticity leads to decreased patient satisfaction, with limited and ineffective oral pharmacotherapy available to treat MS spasticity [39].
MS spasticity therapy is used to improve functional ability, assist rehabilitation, avoid contractures, and relieve discomfort in people with MS. The only use of cannabinoids in neurological disorders and the only complementary medicine intervention with high-level evidence for efficacy in MS is pharmaceutical cannabinoids for spasticity, according to most recent studies [40][41].
The most prevalent and available treatment for MS spasticity is multimodal [38], which combines non-pharmacological and pharmaceutical therapies. The majority of current therapy approaches result in patient dissatisfaction. A new cannabis-based pharmaceutical option with different administration methods has been created. Surprisingly, most studies revealed that topical cannabis was most commonly used for treating MS spasticity because of its pharmacokinetic qualities, although smoking or vaping was the most popular strategy in other studies [42][43]. THC and THC: CBD is the most commonly used cannabinoid to treat spasticity, according to reviews by Ben Amar, Koppel et al., Lakhan, Rowland, and Krast et al. [40][44][45][46].

1.1.2. MS-Related Pain

MS is frequently linked to pain [47]. Pain has long been recognized as a significant element in MS patients’ overall health-related quality of life (HRQoL). Patients with MS who have pain have reported decreased HRQoL, as well as physical and emotional dysfunctions [48][49]. Neurological injury, as well as neurological dysfunction and incapacity, might be the source of severe discomfort [50]. Continuous central neuropathic pain, intermittent central neuropathic pain, musculoskeletal pain, and mixed neuropathic and non-neuropathic pain are all examples of pain associated with MS [49]. Despite significant advancements in providing novel therapeutic techniques for the symptomatic treatment of MS, such as pain, the present therapeutic modalities are insufficient to meet the needs of patients [50][51].

1.1.3. MS-Related Tremor and Ataxia

MS affects the cerebellum and its efferent and afferent pathways, causing tremors, ataxia, and dysarthria in both acute and chronic symptoms [52]. More than 80% of MS patients have tremors or ataxia at some point during their illness [53]. Several pharmacotherapies for the management of tremors or ataxia associated with MS are available, but they are often ineffective [52][54]. Because of the absolute and comparative efficacy and acceptability of pharmaceutical treatments are inadequately recorded, a Cochrane review of six randomized controlled studies for the management of ataxia in MS was unable to provide any recommendations [55]. Furthermore, several randomized controlled studies have looked at the effect of cannabis extracts on these symptoms, but they have concluded that cannabinoids are useless in treating MS tremor and ataxia [40][55][56][57]. As a result, it is prudent to seek out novel treatments.

1.1.4. Bladder Dysfunction in MS

In MS patients, lower urinary tract dysfunction is a prevalent symptom. It usually appears in the later stages of the disease. In total, 50–90% of MS patients develop this symptom after 6 years of disease [58][59][60], which is primarily attributable to a neurogenic overactive bladder [61]. Urinary urgency and urge incontinence can hurt a patient’s quality of life and cause immobility. Anti-cholinergic and intermittent self-catheterization may be beneficial in the early stages [62]. A total of four reviews looked at the effect of cannabis on MS bladder function symptoms [40][44][46][63].

1.1.5. MS-Related Sleep Disorders

One of the most prevalent symptoms among MS patients is sleep disturbances [64]. The most common causes of MS sleep problems are multifunctional, and they are linked to immunotherapy and symptomatic therapies, as well as MS-related symptoms such as pain and exhaustion [65]. Patients with untreated sleep disturbances are at a higher risk of developing diseases, which can have a long-term impact on their health [66][67][68]. Three studies looked into the impact of cannabis on MS sleep problems. However, no conclusion was reached regarding the clinical effects of cannabis in MS patients with sleep difficulties [44][46][63].

1.1.6. Health-Related Quality of Life in MS Patients

HRQoL (Health-related Quality of Life) is a multidimensional perception that encompasses physical, emotional, mental, and social functioning [69]. MS patients have been found to have a lower HRQoL than the general population. The detrimental influence of illness symptoms on daily living performance could explain the worse HRQoL associated with MS [70][71]. In MS patients, the influence of cannabis on HRQoL was investigated, with inconsistent results [46][54][72].

1.1.7. MS-Related Disability and Disability Progression

Progression MS is a disability-causing disease that is characterized by relapsing-remitting neurological episodes [73]. Progression is linked to inadequate treatment and diagnosis, which results in demyelination, axonal and neuronal loss, and various cognitive, sensory, and motor problems [73][74]. It occurs as a result of central nervous system lesions and is driven by central inflammatory and other neurodegenerative effects that underpin irreversible disability. Many studies looked at the impact of cannabis on MS impairment and signs of disability progression [46][63][72][75]. The majority of these reviews did not focus on MS disability, and it was treated as a secondary result with no conclusions about cannabinoids’ impact on it.
 
 

2. Cannabinoid Agents for the Treatment of MS

2.1. Nabiximols

Nabiximols is the generic name for Sativex®, an oromucosal spray containing a 1:1 molecular ratio of THC and CBD (Nabiximols (c), Figure 1) [76]. It has been licensed in several countries for the treatment of severe spasticity in MS patients [5]. The THC, CBD, and the small number of other constituents of the plant extract, including other cannabinoids and terpenoids dissolved in ethanol, make up around 70% of the constituents in Nabiximols [76]. There are 2.7 mg, 2.5 mg, and 0.04 g of THC, CBD, and ethanol, respectively, in each dose of oromucosal spray. Its administration has a favorable pharmacokinetic profile, with fewer first-pass effects and a low plasma concentration, resulting in the avoidance of psychoactive effects that are caused by smoked cannabis [76][77][78]. Furthermore, its maximum plasma concentration would rise gradually within 2–4 h after administration, while the quick onset effect will appear after 15–40 h, making treatment adjustments easier [77]. The synergistic interaction is based on a low-dose combination of THC and CBD, which results in reduced euphoric effects and improved cannabinoid-mediated anti-spasticity therapeutic benefits [76]. According to much research, starting therapy with a 14-day dose titration period is recommended to reach up to 12 sprays as the highest dose per day [78]. Individual dose distribution across a day, as well as dose change over the treatment course, is possible depending on the intensity of the disease. The recommended maximum daily dose is 12 sprays with at least 15 min between each spray [77]. Nabiximols were tested in MS patients with a variety of symptoms, such as stiffness, pain, tremor, and bladder function, in several clinical investigations [56][79][80][81]. Nabiximols were found to have good effects on spasticity, pain, and quality of life in MS patients in the majority of trials (Table 1) [56][79][80][81].

This entry is adapted from the peer-reviewed paper 10.3390/life12050682

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