The articles included in this study for full review cover a range of publications addressing the evaluation of several cytokines both at central and peripheral levels, in animal models and in studies conducted in patients with problematic drug use. These studies also cover different stages of the addictive process, extending from acute drug exposure, to short- or long-term administration/use, withdrawal and drug reinstatement. For a comprehensive understanding of the results, they were grouped according to the type of substances administered/used and according to the type of administration and period evaluated.

After full-text analysis, a pool of 62 publications were considered eligible. Within these, we found 41 publication that evaluated cytokines in the CNS and 18 publications that evaluated cytokines at the peripheral level (Figure 2A). Only three studies evaluated cytokines both at central and peripheral level (Figure 2A). We also analyzed the distribution of cytokines in all the elected studies and found that 17 different cytokines had been evaluated in at least one study (Figure 2B), while most studies addressed several cytokines simultaneously. As expected, the most studied cytokines were the classical pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. The TNF-α profile was evaluated in 47 articles, while IL-6 and IL-1β were both evaluated in 34 articles. As for IL-10, IFN-γ, IL-4, and IL-2, they were evaluated in 16, 10, eight, and five articles, respectively. The cytokines Il-1α, IL-5, and IL-17 were investigated in only two studies. The remaining cytokines—IL-7, IL-8, IL-9, IL-12, IL-15, IL-18, and IFN-α—were addressed in just one publication each (Figure 2B).

To analyze the results reported in the different studies, we have categorized them by type of exposure and/or evaluation timepoint, which allowed four different categories addressing: (i) acute exposure (19 publications); (ii) chronic (mid- or long-term) exposure (27 publications); (iii) withdrawal/abstinence (nine publications); and (iv) reinstatement (five publications; Figure 2C). This categorization is reflected in Tables 1–5 and Supplementary Tables 1–3 and described in detail in the following subsections.

For reading simplification, significantly altered cytokines are referred to as increased/decreased (or equivalent adjectives), however, this implies always that a comparison to an adequate control group was verified.

Drug use often refers to episodic or recreational administration of psychoactive substances (Kuhar, 2012). The effects of acute exposure to psychostimulants can either refer to the adverse effects that result from a single dose or from multiple dosing in a short period of time (i.e., binge drug exposure). Among the 19 studies that evaluated the acute effects of psychostimulants in the cytokine profile, nine used a protocol of a single dose administration (Kelly et al., 2012; Seminerio et al., 2012; Nader et al., 2014; Frank et al., 2016; Gubert et al., 2016; Lewitus et al., 2016; DiCaro et al., 2019; Wang B. et al., 2019; Montesinos et al., 2020) (Tables 1, 2 and Supplementary Table 1) and 10 used a binge pattern protocol (Robson et al., 2013; Urrutia et al., 2014; Coelho-Santos et al., 2015; Frau et al., 2016; Ghanbari et al., 2019; Wang B. et al., 2019; Gou et al., 2020; Canedo et al., 2021; Hadizadeh-Bazaz et al., 2021; Kobeissy et al., 2022) (Tables 1, 2 and Supplementary Table 1). All these studies were conducted in rodent models.

The studies that used single exposure, evaluated only the central levels of cytokines. Upon methamphetamine (Meth) administration, several authors reported an increase in at least one of the classic pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, in different brain regions [Nucleus accumbens (Nacc), the prefrontal cortex (PFC), the ventral tegmental area (VTA), the striatum and the hypothalamus] (Kelly et al., 2012; Seminerio et al., 2012; Nader et al., 2014; Frank et al., 2016; DiCaro et al., 2019) (Table 1). However, other studies reported that these cytokines were not altered in the hippocampus, PFC and Nacc, after a single administration of Meth or amphetamine (Amph) (DiCaro et al., 2019) (Table 1), and a few other studies reported asymmetric results across brain regions (Kelly et al., 2012; Gubert et al., 2016; Wang B. et al., 2019) (Table 1 and Supplementary Table 1). Only two studies addressed central cytokines after a single dose of cocaine, showing unaltered TNF-α levels in the ventral striatum and unaltered IL-1β in the hippocampus (Lewitus et al., 2016; Montesinos et al., 2020) (Table 3). Collectively, these studies evidence that drug-induced cytokine changes are region-dependent, which was confirmed by studies that evaluated the same cytokine in different regions (Kelly et al., 2012; Frank et al., 2016; Gubert et al., 2016; Wang B. et al., 2019) (see Table 1 and Supplementary Table 1). Of note, a number of other variables may also justify the differences observed between studies, such as differences in drug dosing, routes of administration, time-points of evaluation and the methodology used for cytokine quantification. These methodological differences are visible in Tables 1, 3 and Supplementary Table 1. Within these factors, dosing seems to strongly contribute to data heterogeneity, as studies that used low doses mostly showed no differences in cytokine levels (DiCaro et al., 2019; Wang B. et al., 2019) (Table 1), while studies that used higher doses showed increased TNF-α, IL-6 and IL-1β (Kelly et al., 2012; Seminerio et al., 2012; Nader et al., 2014; Frank et al., 2016) (Table 1).

Focusing on studies using binge patterns of administration, we found nine studies evaluating cytokines at the central level and just one evaluating circulating cytokine levels. In rodents, binge Meth administration resulted in cytokine changes similar to those reported for single dosing: (i) one study observed increased expression of TNF-α and IL-1β in both the striatum and the hippocampus (Canedo et al., 2021), (ii) two studies reported increased TNF-α (Coelho-Santos et al., 2015) or IL-6 in the striatum (Robson et al., 2013); and (iii) another study showed increased IL-6 and TNF-α in the mPFC, caudate putamen (CPu) and hippocampus (Gou et al., 2020) (Table 1). Additionally, two of the studies reviewed also reported persistently increased TNF-α levels past 7 and 12 days of Meth binge administration (Ghanbari et al., 2019; Hadizadeh-Bazaz et al., 2021) (Table 1). However, other authors reported no differences in the expression of TNF-α and IL-6 in regions like the hippocampus, PFC, CPu, and the Nacc (Wang B. et al., 2019; Canedo et al., 2021), as well as no differences in IL-1β in the striatum (Canedo et al., 2021) (Table 1).

Also, regarding binge administration but of MDMA, one work showed increased TNF-α and IL-1β levels in the CPu (Frau et al., 2016) (Supplementary Table 1).

As verified in the studies using single dosing, the heterogeneity of results observed for TNF-α, IL-6, and IL-1β under binge schedules were impacted by the same variables. Also in this case, studies using low doses mostly showed no impact in TNF-α, IL-6, and IL-1β levels (Wang B. et al., 2019; Canedo et al., 2021), while those using higher doses reported increased levels for these cytokines (Coelho-Santos et al., 2015; Ghanbari et al., 2019; Gou et al., 2020; Hadizadeh-Bazaz et al., 2021) (Table 1).

Additionally, two cytokines were evaluated in single studies (after Meth exposure): one study reported an increase in the expression of IL-15 in the striatum after binge administration (Urrutia et al., 2014) (Table 1) and one study reported no changes in IL-1α after single administration (DiCaro et al., 2019) (Table 1).

A single study evaluated circulating cytokines after binge Meth administration, reporting augmented expression of IL-1β, IL-6, and IL-10 (Kobeissy et al., 2022) (Table 2). Of note, within the pool of studies reviewed in this section, none evaluated central and peripheral levels of cytokines simultaneously.

Taken together, these results revealed that (i) nine (out of thirteen) studies evaluating TNF-α, showed increased levels; (ii) seven (out of nine) studies evaluating IL-1β reported increased levels; and (iii) five (out of eight) reported increase IL-6 in at least one brain region. Based on this, one can concluded that IL-6, TNF-α, and IL-1β were the most investigated cytokines in acute/binge exposure to psychoactive substances and that drug-induced variations in cytokines are region- and dose-dependent. As we found only a single study reporting on circulating cytokine levels, one can only concluded that more studies at the peripheral level are clearly necessary to understand how circulating cytokines vary with exposure to psychostimulants and how they relate to central cytokine levels.

In this section, we analyzed studies reporting on the effects of repeated administration (over a variable number of days) of psychoactive substances in cytokine levels, either at the central or peripherally. Importantly, repeated administration of psychostimulant may result in substance use disorder and unexpected system adaptations (Nestler and Luscher, 2019).

A total of 28 studies evaluating the short- and long-term effects of psychostimulant administration were considered. Eighteen reported on changes of cytokines in the brain, eight in the blood and two studies evaluated cytokines at both central and peripheral levels (Tables 1–5 and Supplementary Tables 1–3).

Goncalves et al. (2017) showed an increase in the expression of TNF-α in the striatum and hippocampus after seven days of self-administration, but not of IL-1β (Table 1). Other authors reported increased IL-1β in the hippocampus after 4 days of an escalating regimen of Meth (Liskiewicz et al., 2019) (Table 1). All four studies that used protocols of short- or long-term administration of other amphetamines, reported an increase in several cytokines such as TNF-α, IL-1β, IL-6, IFN-γ, IL-4, and IL-10, in the striatum or the frontal cortex (El-Sayed El-Sisi et al., 2016; Shin et al., 2016; Valvassori et al., 2018) (Supplementary Table 1). Gubert et al. (2016) reported that IL-1β and TNF-α levels were unaltered in the PFC and hippocampus after repeated amphetamine administration, while in the striatum TNF-α was also unaltered, but IL-1β was increased (Supplementary Table 1).

Studies that evaluated changes in central cytokines as a result of repeated cocaine exposure consistently showed increased IL-1β, TNF-α, and IL-6 (Lewitus et al., 2016; Mai et al., 2018; Montesinos et al., 2020; Chivero et al., 2021) and reduced IFN-γ (Mai et al., 2018) (Table 3). In these studies, performed in rodent models, the brain regions examined were the striatum, the cortex and the hippocampus (Lewitus et al., 2016; Mai et al., 2018; Montesinos et al., 2020; Chivero et al., 2021) (Table 3). Of note, Chivero et al. (2021) also showed higher IL-1β levels in human postmortem frontal cortices (Table 3).

Consubstantiating the results already reported for cocaine and amphetamines, several studies using rodent models of long-term administration of methylphenidate, also reported increased IL-1β and TNF-α in the hippocampus (Motaghinejad and Motevalian, 2016, 2022; Motaghinejad et al., 2016a,b,c, 2017; Schmitz et al., 2017; Ebrahimzadeh et al., 2019). Schmitz et al. (2017), further reported an increase in IL-6 levels in the hippocampus after methylphenidate administration (Table 5).

At the peripheral level, in rats, one study showed that TNF-α, IL-6, and IFN-γ levels were not affected by long-term Meth self-administration (Mata et al., 2015) (Table 2). Similarly, and also in rats, long-term administration of lisdexamfetamine, did not affect TNF-α, IL-1β, and IL-10 serum levels (Bristot et al., 2019) (Supplementary Table 2). However, in mice, repeated Meth administration resulted in increased circulating levels of TNF-α, IL-1β, and IL-18 (Wang et al., 2022) (Table 2).

Of note, Kuo et al. (2018) analyzed several cytokines in patients that met the criteria for Meth dependence and reported an increase of IL-1β, IL-2, IL-4, IL-6, and IL-10, 3 days after the last dosing (Table 2). This same study reported that IFN-γ, TNF-α, and IL-8 were not altered and that IL-5 was decreased (Kuo et al., 2018) (Table 2). Opposing to these results, other authors reported that IL-6 was not altered in the plasma and PBMCs of Meth-dependent patients with a recent dosing (72 h) (Jiang et al., 2016), while a another study presented increased TNF-α levels in the serum of Meth-dependent patients that were about to start a detoxification treatment (Shen et al., 2020) (Table 2).

Also at the peripheral level, studies that investigated variations of circulating IL-6 and IL-10 in patients with cocaine dependency reported either an increase in both cytokines relative to healthy participants (Pianca et al., 2017) or no changes in these two cytokines and TNF-α at the peripheral level (Ribeiro et al., 2021) (Table 4).

As already referred, only two studies addressed how psychostimulants affect cytokine levels at both peripheral and central levels. Both studies used a long-term administration of D-amphetamine in rats, and showed similar results for cortical, striatal (but not hippocampal) and circulating cytokines, i.e., increased levels of IL-4, IL-10, IL-6, and TNF-α (Valvassori et al., 2015, 2019). IL-1β was unchanged either at central or peripheral level (Valvassori et al., 2015, 2019) (Supplementary Table 3).

Taken together, these studies reveal that when evaluating short- and long-term effects of repeated exposure to psychostimulants, the target cytokines were again IL-6, TNF-α, and IL-1β. At the central level: (i) 13 out of 14 studies showed an increase in TNF-α levels in at least one brain region; (ii) four out of five studies reported increased IL-6, and (iii) all the twelve studies addressing IL-1β reported an increase. At the peripheral level: (i) two out of five studies presented an increase in TNF-α and IL-6, and (ii) two out of two studies reported an increase in IL-1β and IL-10. Interestingly, none of the two studies that evaluated the IFN-γ levels reported changes in this cytokine.

In summary, despite some variability, most of the cytokines evaluated seem to be increased in the brain after short and long-term exposure to psychostimulants, with more robust results for TNF-α, IL-6, and IL-1β. At the peripheral level there is a clear need for further investigation. Importantly, the few studies that analyzed cytokines both at the peripheral and central levels, reported similar results for the cytokines evaluated in both compartments.

The withdrawal period encompasses a disruption in drug intake, in which one develops distressing feelings and strong physiologic reactions (Kuhar, 2012). A correct management of this period is critical to prevent drug relapse (Kuhar, 2012). In this context, understanding how cytokine levels impact on anxiety and impulsivity, critical factors for relapse, may contribute to more successful therapeutic approaches.

Within the pool of studies obtained for review that addressed the cytokine profile at the withdrawal from psychostimulants, we found 10 studies reporting on central cytokine levels, nine studies analyzing circulating levels, and one evaluating them both at central and peripheral levels (Tables 1–4 and Supplementary Tables 1, 3).

When considering studies that evaluated cytokines, at the central level, during withdrawal from Meth, five publications reported increased TNF-α in the hippocampus, striatum, substantia nigra and PFC (Jiang et al., 2014; Shin et al., 2016; Beirami et al., 2017; Goncalves et al., 2017; Namyen et al., 2020), while one publication showed decreased TNF-α in the frontal cortex and unaltered TNF-α in the amygdala and striatum (Stolyarova et al., 2015) (Table 1 and Supplementary Table 1). Other authors, also found unaltered TNF-α in the hypothalamus (Loftis et al., 2013) (Table 1). Of note, differently from other publications that resorted to shorter administration periods, i.e., 5–15 days (Jiang et al., 2014; Beirami et al., 2017; Goncalves et al., 2017; Namyen et al., 2020), Stolyarova et al. (2015) administered Meth for 4 weeks and evaluated cytokine levels 17 days after the last Meth administration, which may justify the divergences in reported data (Table 1).

Focusing on IL-1β, we identified two studies showing an increased expression in the substancia nigra, hippocampus and PFC (Jiang et al., 2014; Namyen et al., 2020), and two studies showing decreased IL-1β in the striatum and frontal cortex (Stolyarova et al., 2015; Goncalves et al., 2017) (Table 1). Additionally, three studies reported that IL-1β was unaltered in the hippocampus, hypothalamus, amygdala and striatum at the withdrawal from Meth (Loftis et al., 2013; Stolyarova et al., 2015; Goncalves et al., 2017) (Table 1). Again, these studies used different Meth doses (ranging from 0.3 to 20 mg/kg) and different administration periods, which invalidates direct comparisons.

Within the studies that evaluated the pro-inflammatory cytokine IL-6, one work showed increased levels in the hippocampus and PFC during the Meth withdrawal period (Beirami et al., 2017) (Table 1) and another showed its increase in striatum during withdrawal from para-methoxy-methamphetamine (Shin et al., 2016) (Supplementary Table 1). Other two studies reported that at Meth withdrawal IL-6 was unaltered in the hypothalamus, amygdala and striatum (Stolyarova et al., 2015; Namyen et al., 2020) (Table 1). Again, Stolyarova et al. (2015) reported the opposite effect in the PFC, showing a decrease in IL-6 expression during the withdrawal period (Table 1).

In addition, one of the publications analyzed, revealed unaltered levels of IFN-γ in the hypothalamus (Loftis et al., 2013) (Table 1), while Shin et al. (2016) (Supplementary Table 1) reported an increase in this cytokine in the striatum. Upon that, two studies reported unaltered IL-10 in the hypothalamus, amygdala and striatum (Loftis et al., 2013) and decreased IL-10 in the PFC after Meth withdrawal (Stolyarova et al., 2015) (Table 1). Lastly, IL-2 levels were seen increased in the hypothalamus (Loftis et al., 2013) (Table 1).

When addressing studies that evaluated cytokines during withdrawal from cocaine: (i) three studies reported unaltered TNF-α levels in the ventral striatum, hippocampus and mPFC (Lewitus et al., 2016; Mai et al., 2018; Zhu et al., 2018) (Table 3); (ii) one study reported that IL-6 was increased in the hippocampus (Mai et al., 2018); (iii) another that it was unaltered in the mPFC (Zhu et al., 2018); and this last study also showed that IL-1β levels were unaltered in the mPFC (Zhu et al., 2018) (Table 3). The levels of IFN-γ were described as decreased at earlier cocaine withdrawal (3 days after last administration) and as unaltered in longer periods of withdrawal (7 and 14 days after last administration) in the hippocampus (Mai et al., 2018) (Table 3).

At the peripheral level, opposing results were reported. In Meth abstinent patients, one study showed that IL-1β levels were unaltered in the plasma (Kohno et al., 2018), while another showed that IL-1β was increased (Kuo et al., 2018) (Table 2). The same was observed for TNF-α, one study reported unaltered levels (Kuo et al., 2018) and two studies reported an increase (Luo et al., 2022; Re et al., 2022) (Table 2). Opposing results were also described for IL-10, with Kohno et al. (2018) claiming that IL-10 was unaltered in Meth abstinent patients, and Kuo et al. (2018) reporting that IL-10 was decreased in the plasma of Meth abstinent patients (Table 2). Interestingly, Re et al. (2022), showed that IL-10 levels were unaltered in the plasma of patients in early periods of withdrawal (7–15 days and 3 months), but increased after 1 year of Meth withdrawal (Table 2).

For IL-6 and IL-2 reported data were consistent, showing an increase in these cytokines in three studies evaluating Meth abstinent patients (Kohno et al., 2018; Kuo et al., 2018; Re et al., 2022) (Table 2). Furthermore, for IL-2, similar results were observed in rats (Li et al., 2021) (Table 2).

Other cytokines were also evaluated in Meth abstinent patients, showing an increase in IL-4, IL-1α, IL-18, IL-12, IL-7, and IL-5, a decrease in IL-8 and IL-9, and unaltered levels of IFN-γ and IL-5 as measured in the serum (Kuo et al., 2018; Luo et al., 2022; Re et al., 2022) (Table 2). The strong level of variation observed among different studies may be attributable to differences in the target populations, since most were recruited from rehabilitation centers in China and Taiwan.

Regarding the studies performed in cocaine abstinent patients, one study evaluated the serum cytokine levels in adolescents, at different time-points of the withdrawal period, and observed that initially the levels of TNF-α and IL-6 were decreased, but after a longer period of abstinence, the levels of both cytokines were reestablished (Levandowski et al., 2016b) (Table 4). Another study, also in adolescents, showed unaltered IL-6 after a similar period of cocaine withdrawal in the serum (Pianca et al., 2017), and two studies reported an increase in IL-6 at a similar time-point, but in women meeting the criteria for cocaine (crack) dependence (Levandowski et al., 2016a; Zaparte et al., 2019) (Table 4). Yet in cocaine abstinent patients, different studies addressing circulating levels reported: (i) an increase in TNF-α (Zaparte et al., 2019); (ii) increased IL-10 in adults (Levandowski et al., 2016b; Zaparte et al., 2019); (iii) unaltered IL-10 in adolescents (Pianca et al., 2017); (iv) increased IFN-γ, IL-2 and IL-17 in PBMCs (Zaparte et al., 2019); (v) decrease IFN-γ, IL-2 and IL-17 in the serum (Levandowski et al., 2016b); and (vi) augmented IL-4 in two studies (Levandowski et al., 2016b; Zaparte et al., 2019) (Table 4).

A single study addressed cytokines both at central and peripheral levels at withdrawal, using a binge protocol of amphetamine (3 × 1 mg/kg, 3 h apart) for six consecutive days, and reporting increased TNF in the striatum and in serum, and unaltered TNF-α in the hippocampus (You et al., 2020) (Supplementary Table 3).

Taken together, at central level: (i) five out of 10 studies showed an increase in TNF-α and only one reported decreased levels; (ii) four out of seven showed increased IL-6 and IL-1β; and (iii) one out of two presented a decrease in IL-10 levels. At the peripheral level, (i) three out of six studies reported an increase in TNF-α: (ii) six out of eight showed an increase in IL-6; (iii) one out of three reported increased IL-1β; (iv) two out of seven presented increased IL-10; (v) two out of four showed an increase in IFN-γ; (vi) three out of four presented increased IL-2; and (vii) one out of two reported increased IL-17 (see also Figure 3). Up on that, four studies evaluated peripheral levels of IL-4, and all reported increased levels. For all the cytokines evaluated at peripheral level, with an exception of IL-4, only one study reported decreased levels.

As described above, the pool of studies that reported data on how withdrawal from psychostimulants affect the cytokine profile, described very heterogeneous results. These may be influenced by several parameters that differ between the studies such as dosing, age of use, or other unreported pathologies; however, the period of withdrawal in which cytokines were evaluated seems to be a powerful modulator of the outcome. This is confirmed in studies that evaluated cytokine profiles in different withdrawal periods and timepoints (Jiang et al., 2014; Levandowski et al., 2016b; Mai et al., 2018; Re et al., 2022).

The high rates of relapse are a major obstacle in the treatment of drug addiction (Kuhar, 2012). Therefore, it is important to address also how relapse itself impacts on cytokines. This can be nicely investigated using animal models of reinstatement (Kuhar, 2012), which are considered a measure of relapse in drug intake.

Among the four studies that evaluated cytokines after psychostimulants reinstatement, two studies measured cytokines in the brain (Brown et al., 2018; Karimi-Haghighi et al., 2020) and two studies in the blood (Gupta et al., 2018; Li et al., 2021) (Tables 1–4). No studies evaluating simultaneously cytokines at central and peripheral level were found.

One of the reviewed studies evaluated the levels of TNF-α, IL-10, IL-1β, and IL-6 in the PFC and hippocampus of rodents, after reinstatement with two different doses of Meth (0.25 or 0.5 mg/Kg) (Karimi-Haghighi et al., 2020) (Table 1). The levels of TNF-α and IL-10 were increased in both brain regions after reinstatement following the highest Meth dose. The levels of IL-1β were increased with both reinstatement doses, but only in the PFC. No changes were reported for IL-6. At the central level, another study, also in rodents, showed increased IL-1β in the VTA after a cocaine challenge, but no differences in TNF-α levels (Brown et al., 2018) (Table 3).

Lastly, Li et al. (2020) showed that in patients suffering from Meth use disorder, a Meth challenging-dose increased IL-6 levels within 360 min of Meth infusion (Table 2). The same study showed that TNF-α levels were not affected at that time point (Li et al., 2020). Gupta et al. (2018), on the other hand, showed in adult cocaine users, that a cocaine challenging does not seem to affect IL-6 levels in the serum at 6 h, 24 h, and 6 days past cocaine (Table 4).

Based on the reduced number of studies addressing cytokines at reinstatement and the variability on reported data, the only possible conclusion is that a strong research effort is yet necessary in the field.

As already discussed this scoping review is limited by a reduced number of studies addressing cytokines simultaneously at central and peripheral levels and by methodology differences. However, it is also important to highlight that drug users are highly heterogenous populations, not always sufficiently characterized, and most likely suffering from stress and mood disorders that can also affect the cytokine profile and impact on the data reported (Montagud-Romero et al., 2022). Sex differences can also strongly affect cytokine profiles, which was not explored. Upon that, several studies have also identified chemokines as possible immunoregulators and this is not addressed in the present study.

In summary, a wide use of arrays for several cytokines should be strongly considered to better determine which cytokines, upon the classical ones, may be involved in the progression from episodic use to the development of addiction. Additionally, a concerted effort should be accomplished to better understand the link between peripheral and central immune players in longitudinal expression profiles of cytokines and its dynamics under exposure to different psychoactive substances.