In the present study, there was a significant increase in the levels of IL-1β, IL-6, IL-8, and TNF-α in patients with cannabis dependency, but no significant differences between the patients and controls were observed in terms of IL-12 and IFN-γ levels. To our knowledge, this is first study to evaluate cytokine levels in patients with dependency. IL-1β, IL-6, IL-8, and TNF-α have important role in proinflammatory process. Many psychiatric disorders are associated with altered cytokine levels. For example, patients with major depression had increased TNF-α, IL-6, and IL-1β levels,27) and antidepressants may reverse the inflammatory process.28) Korczak et al.29) reported that cytokines were responsible for depressive symptoms in patients with type 1 diabetes, and Westling et al.30) found that IL-1β reactivity was associated with symptoms of hostility. Accordingly, Müller et al.31) determined that patients with schizophrenia who were treated with adjunctive nonsteroidal anti-inflammatory agents exhibited significant improvements in total symptoms. Pedrini et al.32) observed that schizophrenic patients exhibit increased levels of IL-6 but decreased levels of IL-10. In another study, the IL-6 levels of acutely relapsed inpatients and first-episode psychosis patients were elevated, but antipsychotic treatment normalized these levels.33)

Despite these findings, the effects of cannabis on the immune system are contradictory. Several factors such as acute or chronic administration, dose and inhalation or digestion of cannabis may contribute to this contradictory. Jan et al.34) suggested that cannabidiol markedly suppressed humoral immunity, and another study found that high-dose cannabis suppressed resistance to infection.35) However, these studies administered cannabis at levels that were much higher than a human could tolerate, 100 to 1,000 times higher than the THC levels in the blood of addicted people.36) At physiological doses, cannabis may stimulate the immune system rather than suppress it, which suggests that this drug has dose-dependent effects.37) Beside cannabis, other illicit drugs have effects on immune system. Narvaez et al.38) reported that patients with crack cocaine use disorder had higher circulating levels of IL-1β, TNF-α and IL-10. Byrd et al.39) suggest that opiate addiction had immunosuppressive role in the brain. CB2 receptors have focus on its role in the immune system.11) Accumulating evidence showed that CB2 receptors are widely expressed in the brain, especially microglia and neurons.40)

The present study also found that patients with cannabis dependency had significantly higher levels of TOS and OSI than did healthy control subjects, although there was no difference in TAS levels. The relationship between psychiatric disease and oxidative stress has been extensively researched, and an imbalanced oxidative status has been implicated in bipolar disorder,18,41) adult attention deficit hyperactivity disorder,17) generalized anxiety disorder,42) and panic disorder.43) However, the role that oxidative stress plays in substance use disorders remains unclear. Sordi et al.20) found positive correlation between reactive substance level and severity of crack cocaine use. Huang et al.21) showed that alcoholic patients had imbalanced oxidative status. THC increases oxidative stress and induces cerebral mitochondrial dysfunction via enhancements in H₂O₂ production in the mitochondria.15) In the present study, IL-6 showed positive correlations with TOS and OSI. The activation of CB1 receptors in astrocytes increases glucose oxidation,44) and IL-6, which is pro-inflammatory, is synthesized by astrocytes. The production of reactive oxygen species is closely associated with the production of energy, and thus is directly associated with mitochondrial activity.45) The brain is the most energy-consuming organ in the body, and the balance between oxidants and antioxidants is very important for brain aging.46) Free radicals in the body induce oxidative damage to cellular components, genetic materials, a process which results in altered cellular function and genetic expression, deteriorated tissue and organ function, and eventually death. In our previous study, we found increased S100B levels in cannabis use disorder, which indicates neuronal damage.47) Regulation of gene expression is a significant mechanism by which chronic exposure to an illicit drug causes long-lasting changes in the brain that underlie the behavioral abnormalities that characterize a state of addiction.48) And oxidative stress and inflammation may have role in this process.

The present study has several limitations that should be noted. First, the sample size was relatively small (34 patients, 34 controls) and all patients were male, so the effects of gender could not be investigated. Second, we measured the cannabis in urine as positive or negative so we didn’t measure the amount of the cannabis that patients used. Next studies should take into consideration the frequency and amount of used cannabis. On the other hand, the present study was the first to evaluate cytokine activity and oxidative status in patients with cannabis use disorder.

In conclusion, the oxidative balance of individuals with cannabis use disorder was impaired and they had higher levels of IL-1β, IL-6, IL-8, and TNF-α, which is a pro-inflammatory cytokine and indicates increased inflammation compared to healthy controls. Thus, these findings suggest that cannabis increased inflammation and impaired the oxidative balance in patients with cannabis use disorder. The inflammation and oxidative stress, which cannabis caused, associated neuronal damage and neuronal death may lead to permanent behavioral abnormalities and clinical implications such as cognitive impairment, anxiety, depression and psychotic symptoms. Next studies should focus on these associations and investigate the role of anti-inflammatory and anti-oxidant treatment in cannabis use disorder.