In the first part of our study, the large number of patients surveyed reported successfully using cannabis outside of the medical system. Despite using varied combinations of THC:CBD as opposed to exclusively high CBD strains, the majority believe, with varying degree of agreement, that cannabis use helps them feel better about their epilepsy condition. One hundred and thirty-six out of 165 cannabis users replied that they did not know the exact content of the cannabis they use, and 29 out of the total number of cannabis users stated that they use multiple types that would probably encompass various ingredients with different purity. In the term of the amount used, patients were unable to quantify the exact amount (in milligrams) of cannabis they were using, which can partially be explained by the fact that the majority of them reported smoking as the primary means of administration which does not allow for precise dosage measurement. Instead, they replied as “indistinct measurement”, or sometimes, they describe it as “one dropper full” or “pea-sized amount”. However, the majority replied they use cannabis at least 1 to 2 times daily (34.5% for those answered once daily and 40.6% for the answers 1 to 2 times per day). They stated that it is finally a matter of availability and that the whole thing depends on socioeconomic reasons that would cause pure forms to be difficult to obtain. Patients surveyed did not have a full clear understanding of the potential risks and benefits of cannabis and its components. They used cannabis that contains varying amounts of THC. Although they stated that some pure preparations, especially “oil”, are available, the cost is still the main hindering factor limiting the use of CBD oil at dosages comparable to those used in clinical trials. Additionally, no commercial CBD oil or other preparations are available in Egypt and, rather, are prohibited.

Generally, epilepsy patients report that cannabis use is helpful for seizures as a way of justifying their recreational use or may be influenced by a strong desire for cannabis to be an effective treatment. In this context, in 2015, a retrospective study done in Colorado highlighted one aspect of self-reporting bias among patients taking medical cannabis for epilepsy treatment. Patients involved in the study moved to Colorado for the purpose of obtaining legal medical cannabis. They were 3 times more likely to report significant cannabis benefit than patients who were native to Colorado. This finding showed that the amount of effort that patients put forth to obtain medical cannabis affects their perception of treatment efficacy [51].

Regarding cannabis sources, it was logic to find out that “dealers” and friends/family members are the source because pharmacy and medical dispensaries are not legalized in Egypt to deal with any commercial or medical cannabis preparations. The majority of patients generally found cannabis more accessible nowadays than before. Gender differences in cannabis use might reflect environmental epidemiologic gender differences in recreational cannabis use, since more men than women use cannabis for recreational purposes in a lifetime sustained manner, and men are more likely than women to be diagnosed as having cannabis use disorder [52,53].

The above findings emphasize the knowledge gap among patients and doctors regarding the exact amount of cannabis and, ultimately, the appropriate dosing for medical usage in epilepsy disorder. Even when highly educated patients intend to use CBD oil similarly to the dosing used in clinical trials for epilepsy, they tend to use a sub therapeutic dose or not understand how much they are actually taking. This limitation in our study is in coherent with the fact that many cannabis dispensaries do mark products with respect to THC and CBD content [50]; however, multiple studies have demonstrated that the labeling can be inaccurate [54,55]. The number of doses per day varied among the participants in the study which is expected as cannabis was not being used as a medication; otherwise, one would expect it to be taken regularly in the same manner as other epilepsy medications. This hinders the evaluation of whether or not cannabis use has a real influence on the course of epilepsy disease. In this context we have encountered no significant differences between the two patient groups in the terms of seizure frequency and severity. Besides, there are many factors that may trigger the use of cannabis products on a different schedule than in the regular clinical trials, which may include cost, poor understanding or misunderstanding of cannabis effect, desire to use cannabis more frequently for recreational reasons, or conversely, desire to avoid using cannabis during the day to avoid feeling “high”.

The potential area where a patient can benefit from cannabis in the treatment of epilepsy is yet far in Egypt. Further studies and education may be beneficial in the future. The responses highlight the wide gap between patients’ desire to use cannabis products for recreational purposes and their knowledge about how to use cannabis as an epilepsy treatment. We propose that future research should be directed to assess the efficacy of physician counseling regarding the risks and benefits of medical cannabis. Indeed, clinical trials are mandatory to decide whether or not cannabidiol is an efficient treatment for epilepsy disease.

In the second part of the current work, we highlighted the link between epilepsy disease and the influence of cannabis use on inflammatory mediators as a putative mechanism of epilepsy. Although the role of inflammation in patients with epilepsy has been widely debated and partly considered as just an epiphenomenon, resulting from seizure-induced damage to the brain or excessive muscular activity, interestingly, the current findings of elevated levels of the inflammatory cytokines; IL-1α, IL-1β, IL-2, IL-6, IL-8, and TNF-α, both in serum and leukocytes gene expression analyses, is in agreement with the previously shown results of elevated cytokines levels in epilepsy patients [1,20,22,40,56,57,58] and moreover, provides direct clinical evidence that the immune system and cytokines mediators are involved in epilepsy disorder.

Generally, there is crosstalk between seizures and inflammatory mediators. Some epilepsy can originate from inflammatory changes or traumatic injuries early in life, ion channel malfunction, as well as metabolic or degenerative diseases [59,60,61]. The involvement of cytokines in the pathogenesis of epilepsy has been suggested by the evidence that limbic seizures increase mRNA of inflammatory cytokines in rodent forebrains [19]. It was also suggested that seizures trigger de novo synthesis of cytokines. An attractive hypothesis postulated that glutamate released from the neurons during seizures activates cytokine transcription in glial cells; however, specific effects triggering the seizures may play a role in this activation such as protein extravasations from the BBB or stress associated events priming glial cells [62,63,64,65]. In the same context, it was demonstrated that both humoral and cell-mediated immunity are more functionally disturbed among persons with the epilepsy than in the general population [66,67,68,69].

The serum and gene expression of the inflammatory cytokines—IL-1α, IL-1β, IL-2, IL-6, IL-8 and TNF-α—showed the highest levels among the “Epilepsy-only” group followed by lower levels in the epilepsy–cannabis users and finally the lowest levels in the healthy controls. Our findings of the lower inflammatory cytokine levels among cannabis users in comparison to the epileptic non-cannabis users are not surprising, and are coherent with previous pre-clinical and clinical studies showing an anti-inflammatory effect of cannabinoids [70,71,72,73]. Interestingly, the anti-inflammatory IL-10 was significantly lower in both epilepsy groups compared to healthy controls; however, it showed a significant higher level in the “Epilepsy + Cannabis” group when compared to the “Epilepsy-only group”. IL-10 possesses an essential regulatory, anti-inflammatory role but the mechanisms that lead to IL-10 production during infection and inflammation are incompletely understood [1]. IL-10 opposes many pro-inflammatory processes during diseases. It may ameliorate immunopathology by preventing inflammation-associated tissue damage [74]. Our finding of increased levels of IL-10 among epileptic cannabis users compared to epileptic-only patients might explain partly the anti-inflammatory effect of cannabis that would serve as a clue for its anticonvulsant effect. However, some studies have demonstrated elevated levels of IL-10 among epileptic patients similar to the pro-inflammatory cytokines [1]. The increased IL-10 in epilepsy patients can be due to counteracting mechanisms to the pro-inflammatory stimuli.

In contrary, IL-4 showed no significant difference between patients and controls nor when the comparison has been drawn in regards to cannabis use. The earliest studies of IL-4 in macrophages showed that it represents an anti-inflammatory agent when administered concurrently or shortly after an inflammatory stimulus, and is capable of downregulating the production of inflammatory cytokines such as TNF [75]. Moreover, IL-4 is not only purely an anti-inflammatory agent, however, as the priming of macrophages with IL-4 followed by pro-inflammatory stimulation can yield an enhanced inflammatory response [76]. In vivo studies have revealed that chronic high dosage or transgenic overproduction of IL-4 results in accumulation of AAMΦs, increased IFN-γ expression, decreased pro-inflammatory cytokine production, histiocytosis, erythrophagocytosis, extramedullary hematopoiesis, and weight loss [77]. Accordingly, it was suggested that the in vivo effects of IL-4 are complex, well regulated, dependent on the local environment, and that they probably intermediate different processes simultaneously in different tissues. The situation is even more complex in the context of the brain, which is clearly affected by IL-4; however, little is known about the ability of this cytokine to access the parenchyma or the nature of its effects on target cells. IL-4 has been studied in microglia and astrocytes within the CNS; nevertheless, the possible role of IL-4 in directly stimulating neurons and oligodendrocytes is poorly understood [78].

Discrepancies of our findings to other studies might result from the post-transcriptional abnormalities of cytokine expression, leading to a lack of correlation between transcript levels and protein levels. Gene expression may be more easily and rapidly affected than systemic cytokine levels [79], and therefore some differences between gene expression and serum levels might be related to the effects of more recent and acute vs. chronic activation of the immune system. Indeed, elevated cytokines may derive from cytokine-producing cells other than peripheral immune cells, such as intra-hepatic or adipose tissue-associated cells [80].