Multiple sclerosis is believed to be an autoimmune demyelinating CNS disease that is triggered by certain environmental or viral triggers on a susceptible genotype of the affected individual [24].

The clinical efficacy of cannabis in the management of multiple sclerosis symptoms remains a matter of debate. Cannabis appears to have a benefit in reducing pain in MS [17]. Nevertheless, another meta-analysis has denied the superiority of cannabis compared to minor opioids in the management of pain [25].

This study was conducted at Mansoura University Hospital and was aimed at evaluating the prevalence of cannabis abuse in multiple sclerosis cases and the effect of cannabis on serum cytokines and symptom improvement in such cases.

In our study, 28 out of 150 MS cases were cannabis abusers (18.67%). This is much lower than the reported percent in the literature. The etiology behind that could be explained by the fact that most MS cases are females, and cannabis abuse in Egypt is more common among males compared to females. The feeling of social disgrace may be the cause in some cases although patient confidentiality was ensured.

In a previous study, the overall prevalence of cannabis use was 39.9% in multiple sclerosis patients [1]. Previous studies reported the prevalence of 43% of multiple sclerosis cases in the United Kingdom [17] and Canada [26].

Patient general demographics did not differ between the study groups, apart from gender, which showed the significantly higher predominance of males. This is due to the fact that most of the cannabis abusers in Egypt are males [27]

Regarding clinical improvement, all studies symptoms showed significant improvement in the MS/cannabis cases compared to MS cases (p < 0.05), apart from sexual dysfunction, bladder symptoms, and visual disturbances. Of note, these last three symptoms also witnessed some degree of improvement, but it was not significantly different from the other group.

As multiple sclerosis cases usually have heterogeneous symptom profiles, it becomes more challenging while studying the effects of cannabinoids on this disease. Therefore, it may be hard to detect the effect on secondary outcomes when symptoms are not found in all study participants.

Likewise, in another study that included 37 multiple sclerosis cases, spasticity diminished by 2.74 points on the Ashworth scale, while pain decreased by 5.28 points on the visual analogue scale after cannabis smoking for 3 days. Nevertheless, cognition was significantly decreased as measured with the Paced Auditory Serial Addition Test [28]. This agrees with our findings regarding pain improvement.

Other researchers reported that 90% of the included MS cases reported improvement in both pain and spasticity [29]. Nevertheless, the other two studies reported no significant improvement regarding spasticity [5, 30].

Another study reported that following cannabis extract intake, the primary symptom score reduced from mean 74.36 to 48.89 and from 74.31 to 54.79 following the placebo (p > 0.05). Spasticity VAS scores were significantly reduced compared to the placebo (p = 0.001) [31].

Another study evaluated the safety, tolerability, and efficacy of two whole plant extracts of Cannabis sativa in multiple sclerosis patients with refractory lower urinary symptoms. After treatment, there was a significant decrease in urgency, frequency, number and volume of incontinence episodes, and nocturia. Moreover, pain, spasticity, and sleep disturbances were also improved. However, daily total voided, catheterized, and urinary incontinence pad weights also decreased significantly on both extracts [32].

Other trials have reported that cannabis could induce bladder function improvement [32], but not tremors [33].

In the current study, the number of relapses within the last five years was significantly lower in the MS/cannabis group (p = 0.001).

It was previously reported that endocannabinoid levels in the CNS might be increased during remission from an immune attack in patients with chronic neuroimmunological diseases. This in turn can limit symptom severity including spasticity and pain [15].

On the other hand, during the attack, there is a decrease in the endocannabinoid levels [34, 35], which may result in neuronal loss due to glutamate excitotoxicity and toxic accumulation of ions such as calcium [36, 37]. The decrease in endocannabinoid levels is attributed to the release of cytokines such as interferon-gamma by infiltrating T cells that disrupts the purinergic P2X7 receptor function which controls endocannabinoid responses by microglia [35]. This loss of endocannabinoid neuroprotection may contribute to nerve damage as a direct effect of the neuroimmune attack [38].

Based on the above findings, it is obvious that cannabis intake might prevent the incidence of relapse as it compensates for the relative deficiency essential for relapse to occur.

In the current study, fifteen cases (53.6%) reported that their symptoms were improved by cannabis. Eight cases strongly agreed that cannabis improved their MS state (28.57%). Besides, 7 cases (25%) agreed with that. Conversely, 8 cases (28.6%) disagreed, while 3 cases (10.7%) strongly disagreed with the same concept. Therefore, there was more tendency to accept cannabis as an effective modality in improving MS symptoms.

Recently, Cofield and his associates evaluated the interest in and use of marijuana before and after multiple sclerosis diagnosis in 5481 participants. The authors reported that 64% of the participants reported cannabis use before diagnosis, while 47% would consider cannabis as a possible supplementary treatment option for multiple sclerosis symptoms. In addition, 91% of respondents believed that cannabis administration should be legalized [39].

When it comes to the serum cytokine profile in our study, proinflammatory cytokines including IL-1, IL-2, IL-6, IL-17, IL-22, TNF, and IFN-γ were significantly elevated in the MS group compared to the MS/cannabis and control groups (p < 0.05). Additionally, anti-inflammatory cytokines including IL-4, IL-10, and IFN-β1 had significantly lower values in the MS group compared to the MS/cannabis and control groups (p < 0.05).

Multiple studies have reported that cannabinoids may slow progressive neurodegeneration [35, 40, 41]. Besides, experimental studies on multiple sclerosis showed that cannabinoids can inhibit the immune response in such cases [38]. These effects are mediated by both the CB1and CB2 receptors [42, 43].

The activation of cannabinoid receptors leads to the production of immunosuppressive molecules. Also, cannabis can control the release of neurotransmitters that lead to changes in the hormonal systems, including sex hormones, leptins, and glucocorticosteroids. These hormones can inhibit lymphocyte activation and cytokine production [44].

Furthermore, cannabinoids can inhibit T cell autoimmunity, antigen-presenting cell function, and production of proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha. It can also control the apoptosis of autoreactive cells [43, 45].

Sexton and his colleagues suggested that chronic cannabis use led to a global decrease of cytokines in both healthy controls and individuals with multiple sclerosis [46]. Conversely, other reports have noticed no changes regarding the levels of IFNc, IL-10, or IL-12 with cannabis administration [47, 48].

Other authors reported that in the presence of COR167 (high-affinity cannabinoid receptor agonist), there was a marked decrease or complete blocking of production of IL-2, IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6, IL-17A, GCSF, and TGF-beta1. Conversely, a very high increase of secretion of IL-10, as well as a lower extent for IL-12, was observed [8]. Most of these findings agree with our results.

IL-17 is secreted mainly from T helper cells, and it plays a crucial role in CNS inflammation, especially in MS [49, 50]. Previous researchers stated that serum IL-17 levels were found to be significantly elevated in MS cases compared to healthy controls [51]. A previous study reported that neutralization of that cytokine resulted in significant attenuation of MS symptoms [52].

Regarding IL-22, it has been incriminated in blood-brain barrier breakdown and subsequent lymphocyte infiltration [53]. It can regulate immunity and contribute to MS severity [54]. Evidence from the existing literature suggests IL-22 dysregulation in MS cases [55] which may lead to astrocyte malfunction [56].

In addition, TNF-α was reported to be significantly overexpressed in MS cases [57]. It is a potent inflammatory cytokine which is secreted from different immunity cells including macrophages, monocytes, and differentiated T cells [58]. However, another study reported that TNF-α may have a dual function in the CNS, as its deficiency led to more inflammation and demyelination in animals [59]. Based on these heterogeneous data, it is recommended to conduct more studies regarding that cytokine to precisely define its role in CNS diseases.

IFN-γ, which is secreted from T cells and natural killer cells, has an important role in the autoimmune pathogenesis of MS. An increase in its levels was detected during symptomatic disease, while it decreased significantly during remission [60, 61]. Moreover, IFN-γ antibody treatment delayed disease progression in a previous study [62].

An IL-1 increase was detected in cases with systemic inflammation and brain damage, along with infections [63]. It induces polarization of T cells toward Th17 cells, which are the key cells in MS [64]. However, other studies showed that IL-1 has a neuroprotective effect mediated by the nerve growth factor [65].

As MS is mainly an autoimmune disease, its role in Th1 cell expansion is thought to share in the pathogenesis of MS. Besides, its levels were also correlated with disease activity [66].

Based on the previous data, a decrease in the levels of the previously mentioned proinflammatory cytokines surely will help improve patient condition and relieve distressing symptoms as experienced in the current study.

On the other hand, IL-4 causes a decrease in the proinflammatory cytokines including IL-1, IL-6, IL-8, and TNF-α [67]. Furthermore, it can inhibit macrophage activity [68]. Animals deficient in IL-4 showed an increased proinflammatory response and axonal injury [69].

Similarly, IL-10 can inhibit the release of proinflammatory cytokines [70]. It was found to decrease the severity of autoimmune diseases in experimental animals through its interaction with IL-21 [71].

IFN-β has shown significant treatment effects in relapsing MS patients by reducing physical disability, exacerbation frequency, and disease activity [72]. It mediates its effects through increasing IL-10 expression, modulating IgG production, and decreasing proinflammatory cytokines [73].

The decrease in the previously mentioned three anti-inflammatory cytokines will have a positive impact on disease progression, as illustrated in our study.

As regards cannabis drawbacks encountered in the current study, sleepiness was the commonest encountered side effect (39.3%), followed by difficulty with concentration (35.7%) and hunger pain (28.6%). Other side effects included feeling hyper (21.4%), loss of balance (10.7%), paranoia (7.1%), nausea (7.1%), weakness (3.6%), and blurred vision (3.6%).

Despite symptom improvement, some side effects must be taken into consideration, especially in multiple sclerosis cases [74]. The potential for cognitive dysfunction is still a concern in cases with preexisting dysfunction. Other physicians expressed their caution regarding cannabis use in the elderly and persons with psychosis [75].

The most common reported side effects include dizziness, euphoria, difficulty with concentration, diarrhea, and dry mouth. In most reviews, these symptoms were described to be mild to moderate in severity [76].

Another study reported that the most common of these side effects were feeling “quiet and mellow” (41%), sedated (35%), euphoric (“giggly,” 27%), “lazy” (23%), and always feel hungry (increased appetite, 29%). Three subjects reported paranoia, another three experienced exaggerated weakness, and one case reported hallucinations [17].

Wade and his coworkers reported that there were no significant adverse effects on cognition or mood and intoxication was generally mild [31].

Our study has some advantages; it discussed the most relevant cytokines involved in the MS pathway. Also, the clinical response was also evaluated as well. We should have evaluated these cytokines in CSF, but it was difficult to convince 150 healthy controls to have a lumbar puncture.

On the contrary, some limitations of the current study are also present. First, it is a single-center study. In addition, cannabis use by patients was for creational not therapeutic purposes. The dose sufficient to improve symptoms was also unknown as all cases did not know the exact dose taken for sure. It is recommended to conduct more studies including more cases from different centers. Also, medical cannabis should be commenced for such cases to determine the effective dose for symptom improvement and to be sure of the different ingredients of the administered drug, as the majority of cannabis in Egypt is of different purity.