The Diagnostic and Statistical Manual of Mental Disorders, fifth Edition (DSM-5) defines substance-related and addictive disorders in two sub-categories: substance use disorders (SUD) and substance-induced disorders. SUD is a chronic and recurrent disorder characterized by increased intake of legal and illicit drugs despite adverse consequences [1,2]. Methamphetamine is a potent central nervous system psychostimulant that affects the brain’s neurotransmitter system. It is highly addictive and neurotoxic to the central nervous system [2,3]. Methamphetamine, also known as “ice” or “crystal,” has seen a steady increase in abuse in recent years, with more than 33 million people worldwide [3].

Methamphetamine use disorder (MUD) is a health emergency for which no effective treatment exists. It has a high prevalence of associated mental and physical health problems [4]. Depression, schizophrenia, Parkinson’s disease, psychosis, and other neuropsychiatric disorders are more likely to develop in methamphetamine abuse, which may be primarily due to methamphetamine-induced neurotoxicity. The mechanisms underlying this neurotoxicity can be oxidative stress, excitotoxicity, and neuroinflammation [3]. Methamphetamine abuse is related to infectious diseases (HIV, hepatitis, etc.), periodontal disease, cerebrovascular events, pulmonary hypertension, stroke, kidney failure, and an increased risk of infection [3]. Methamphetamine devastates host immunity by enhancing the risk of pathogen transmission and exacerbating disease progression [5].

MUD can cause anxiety and depression. In addition, attention, memory, and cognitive problems may occur even during the remission period. Several varieties, including C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-8, interleukin-23, and vascular endothelial growth factor, were shown to be significantly associated with neuropsychiatric outcomes [4]. Exposure to methamphetamine affects both central and peripheral immune system functions, including changes in B and T cell expression, macrophage function, and natural killer cell activation [4]. Methamphetamine-administered mice represented increased macrophage, neutrophil, and proinflammatory cytokine values but low T lymphocyte levels [6].

Studies about psychiatric disease etiologies have focused on inflammation and inflammatory parameters. Immune system changes and subclinical inflammation accompany most psychopathologies [7]. The role of subclinical inflammation in mental illnesses is still unclear. Inflammation is a physiological mechanism acting in tissue injury recovery and infection elimination. However, abnormal responses or chronic inflammation may be pathological [8]. The inflammatory mediators are linked to many psychiatric disorders and contribute to neuroinflammation [3,7-9].

Studies linking inflammation with SUD are available in the literature. Blood biomarker studies are one of the most used methods. However, many of these biomarkers are difficult to collect or expensive to measure routinely, which may limit the practical application in clinic. Platelet (Plt) count, mean platelet volume (MPV), plateletcrit (PCT), white blood cell count, subtypes, and their ratios to each other (neutrophil/lymphocyte rate [NLR], monocyte/lymphocyte rate [MLR], platelet/lymphocyte rate [PLR], basophil/lymphocyte rate [BLR], systemic immune inflammation index [SII], etc.) are inexpensive determinants of inflammation which can be measured easily by a complete blood count [8-14]. CRP is an acute phase reactant produced by the liver and is involved in the inflammatory response. It is used as a biomarker of systemic inflammation in clinical practice [15]. Macrophages and monocytes are vital in synthesizing and releasing proinflammatory and prooxidant cytokines. High-density lipoprotein (HDL) preserves the endothelium from the harmful effects of low-density lipoprotein (LDL) and prevents LDL oxidation. HDL thus exhibits anti-oxidant and anti-inflammatory activities. The monocyte/HDL ratio may be a potential inflammatory and oxidative stress parameter [16]. SII is a much more critical marker in showing inflammation and immune response than PLR and NLR. It is calculated using Plt, neutrophil, and lymphocyte values (SII=Plt×neutrophil/lymphocyte). High SII is related to several diseases’ severity and poor prognosis [11,14,17].

There are studies examining PLR and NLR in patients with methamphetamine, heroin, cocaine, cannabis, and synthetic cannabinoid use disorders [9,10,18,19]. On the other hand, MPV, PCT, MLR, BLR, monocyte/HDL ratio, and inflammatory markers such as SII were not evaluated to confirm the presence of subclinical inflammation in MUD. Overall, limited information is available other than the short-term effects of MUD. Examining the potential role of inflammation in the MUD pathophysiology may help us understand how methamphetamine influences the immune system in the long term, open new avenues of intervention involving the inflammatory system in treatment, and inform and guide public policy.

This study aims to reveal the relationship between inflammatory response and MUD by evaluating routine biochemistry and peripheral hemogram parameters, monocyte/HDL ratio, NLR, PLR, MLR, BLR, MPV, PCT, SII, and CRP in individuals with MUD.

53.9% of the patients were unemployed. There was a significant difference between the patient and control groups regarding education level (p<0.001). Smoking was significantly higher in the patient group compared to the control group (p=0.014). The comparison of the sociodemographic characteristics of the patient and control groups is shown in Table 1.

Table 2 compares the BMI and blood parameters of the patient and control groups. The BMI value of the patient group was significantly lower than the control group (p=0.004, effect size; 0.482). Leukocyte (p<0.001, effect size; 0.696), Plt (p<0.001, effect size; 0.711), PCT (p=0.002, effect size; 0.392), neutrophil (p<0.001), monocyte (p=0.002, effect size; 0.560), and CRP (p<0.001) levels in the patient group were significantly higher than in the control group. NLR (p=0.001), PLR (p=0.004, effect size; 0.483), MLR (p=0.009), SII (p<0.001, effect size; 0.885), and monocyte/HDL ratio (p<0.001) were higher in the patient group than in the control group. The effect size of SII was 0.885.

Table 3 shows the relationship between the daily methamphetamine intake, methamphetamine use duration, SII, BMI, and blood parameters. We observed a significant and positive correlation between daily methamphetamine intake and methamphetamine use duration (p=0.002), PCT (p=0.044), neutrophil (p=0.021), NLR (p=0.001), PLR (p=0.004), MLR (p=0.029), and SII (p<0.001).

A model of age, BMI, methamphetamine use duration (month), and daily methamphetamine intake (gr/day) was created on SII. According to the linear regression analysis results, only the daily methamphetamine intake was effective on SII (p=0.001). A one-unit increase in daily methamphetamine intake elevated SII by 165.53 units. Linear regression analysis of the effect of age, BMI, methamphetamine use duration and daily methamphetamine amount on SII is shown in Table 4.

This study suggests the presence of systemic inflammation in MUD with different markers and variation patterns. It is the first study using routine biochemistry and peripheral hemogram parameters (leukocytes, neutrophils, lymphocytes, monocytes, basophils, MPV, PCT, CRP), monocyte/HDL ratio, NLR, MLR, PLR, BLR, and SII to affirm the subclinical inflammation in adults with MUD through evaluating multiple hematologic parameters.

Methamphetamine addiction is associated with the male gender, a low education level, heavy tobacco use, and increased unemployment [22,23]. Our patient population was male and 53.9% were unemployed. The education level was low, and the majority of the patients were smokers. The behavioral effects of methamphetamine comprise elevated alertness and energy, weight loss, diminished need for sleep, and loss of appetite [24]. In our study, the patient group had a lower BMI than the control group, consistent with the literature.

Although inflammation is crucial to prevent adverse environmental challenges, the inflammatory response can become dysregulated and damage healthy tissues [7,8]. Inflammation is a complex process. Several molecules, including cytokines, acute-phase proteins, and chemokines, directly or indirectly regulate it [7]. Peripheral inflammation may supply neuroinflammation through changes in several organs and tissues. Inflammatory mediators have been linked to numerous psychiatric disorders and contribute to neuroinflammation. Neuroinflammatory processes are often a part of many mental illnesses, such as major depression, bipolar disorder, schizophrenia, or SUD [3,7-9].

Subclinical inflammation and peripheral inflammatory parameters are among the most emphasized areas in recent studies to reveal the etiopathogenesis of psychiatric diseases. Leukocyte (neutrophil, lymphocyte, monocyte, eosinophil, and basophil) levels, MPV, PCT, and CRP values are used to specify an inflammatory response [9,11,12,18,19,25]. NLR, PLR, MLR, SII, and monocyte/HDL ratio are informative parameters that indicate chronic low-grade inflammation [9-11,16,19,25,26]. The literature mentions the role of inflammation in psychiatric diseases such as schizophrenia, mood disorders, obsessive-compulsive disorder, and major depressive disorder [11,26]. In the literature, there are studies on subclinical inflammation in patients with SUD, but the results are inconsistent. NLR was high in patients with cocaine use disorder [10], and PLR and NLR were increased in patients with heroin use disorder [18]. However, NLR and PLR in adults with MUD were low, and this might be related to the possible toxic effects of methamphetamine on the immune system [19]. In our study, the patients’ leukocyte, neutrophil, and monocyte counts; Plt, PCT, and CRP levels; and NLR, PLR, and MLR were higher in the patient group compared to the control group. We observed a significant and positive correlation between the daily methamphetamine intake, methamphetamine use duration, PCT, neutrophil, NLR, and PLR. On the contrary, lymphocyte levels did not vary significantly between the control and patient groups.

MUD is described as causing severe dysregulation of the peripheral immune response [24,27,28]. Pro- and anti-inflammatory cytokine and chemokine expression have been linked to neuronal damage caused by methamphetamine use [29]. Cannabinoid derivatives have anti-inflammatory properties and can modulate immune function [8]. Acute cannabinoid exposure may reduce the cellular immune response, inhibit inflammatory cytokine and chemokine production, and diminish excitotoxicity and neuronal cell damage [30]. Individuals with a history of cannabis use have lower CRP levels (<0.5 mg/dL) compared to current users and never-users [31]. 56,6% of our patients (n=43) had a history of other illicit drug use. Considering that there were cannabis users among them, CRP levels and even other inflammation markers would be much higher.

Macrophages and monocytes are essential in synthesizing and releasing proinflammatory and prooxidant cytokines. HDL performs antithrombotic, anti-inflammatory, and antioxidant activities. It protects the endothelium from the harmful effects of LDL and prevents LDL oxidation [32-34]. The monocyte/HDL ratio may be a novel inflammatory and oxidative stress indicator [16]. SII is a new inflammatory biomarker that accurately reflects the balance between inflammation and immune response [35]. High SII values are associated with disease severity and poor prognosis in many diseases and malignancies [11,14,17]. Patients with major depressive disorder have a high monocyte/HDL ratio which elevates as the severity of depression increases [36]. Recently, the use of SII has been expanded to include psychiatric disorders. SII is elevated mainly in men who express manic episodes and women accompanying depressive episodes [11]. High SII levels have been associated with major depressive disorder [37]. A study on patients with schizophrenia and bipolar affective disorder demonstrated an increased monocyte/HDL ratio and SII [33]. However, we could not find any research on the monocyte/HDL ratio and SII in adults with MUD. We discovered that the monocyte/HDL ratio and SII were higher in the patient group than in the control group. The effect size of SII was 0.885. We found a significant and positive relationship between SII and daily methamphetamine intake. A one-unit increase in daily methamphetamine intake elevated SII by 165.53 units. Our findings reveal the presence of subclinical inflammation in male adults with MUD. The literature reports that methamphetamine disrupts peripheral and central immune functions. Inflammatory cytokines enter the central nervous system and stimulate glial cells to produce similar inflammatory cytokines, which trigger addictive behavior and neurotoxicity [29,38].

Endothelial cell permeability, neutrophils, macrophages, and Plt are all part of the first-line inflammatory response, and their role in inflammation is becoming increasingly important [39]. Plt and PCT levels contribute to vascular events such as atherosclerosis and thrombosis [12,13]. In the current study, the patient group’s Plt and PCT values were significantly elevated compared to the control group. PCT showed a significant positive relationship between daily methamphetamine intake and SII. Methamphetamine increases endothelial surface antigens, which have a crucial role in endothelial damage and are a risk factor for death due to cardiovascular disease [27]. Cardiac complications such as malignant hypertension, arrhythmia, aortic dissection, hemorrhagic stroke, myocardial infarction secondary to vasospasm, and methamphetamine-related cardiomyopathy play a vital role in methamphetamine-related morbidity [24,40,41].

Cytokines, chemokines, and cell adhesion molecules might be involved in methamphetamine-induced neuron damage and cognitive function loss [42]. Ibudilast is a phosphodiesterase and glial activation inhibitor. It alleviates the acute proinflammatory effects of methamphetamine and reduces methamphetamine locomotor activity, addiction, and relapse [30,42-44]. Minocycline, a tetracycline group antibiotic, may lessen the reward effects of methamphetamine and decrease methamphetamine-induced dopamine release, relapse, and neurotoxic effects [30,44]. Ceftriaxone, a β-lactam group antibiotic, reduces cocaine and methamphetamine craving [44]. These studies suggest that drugs that diminish methamphetamine-induced neuroinflammation can also reduce methamphetamine-related neurodegeneration. Thereby, they can enhance neurocognition and treatment results in methamphetamine addiction.

We recommend long-term follow-up of these patients and evaluation of those who develop organic pathology and additional psychopathology to reduce morbidity and mortality. This will help us to understand how immune-inflammatory response enhances the comorbid disease in methamphetamine users and will improve our knowledge of the pathogenesis of these disorders.

The strengths of this study are the strict exclusion criteria, the use of interview-based diagnostic evaluations, the evaluation of the participants by an experienced psychiatrist, the inclusion of important immune system-related variables, the prospective nature of the study, and the compatibility of our findings with the literature. Although addiction is a comorbid disease, excluding patients with major comorbidities is a strength and a limitation of our study. The limitations of our study are that it is cross-sectional, some of the data are based on self-report, only male participants were included, and immune system-related variables, such as cytokines, were not included in our analysis. In addition, smoking may also increase the levels of inflammatory biomarkers. Here, we aimed to reflect a real example of society. It is essential to remember that the study’s results may only represent part of society.