The effect of aerobic combined resistance training on the levels of plasma IL-1β, TNF-α, and IL-6
A previous study reported that exercise protects an individual against the MA-induced systemic increase of pro-inflammatory cytokines levels. In addition, exercise can prevent BBB destruction and improve related microenvironmental changes to reduce MA-induced neurotoxicity . Our research found that eight weeks of aerobic combined resistance training can significantly reduce the levels of IL-1β, TNF-α, and IL-6 in peripheral blood. There was a slight decrease in the plasma level of IL-1β in the CC group on the 8th weeks, but the decline is not obvious. On the other hand, the CE group had a smaller decrease after eight weeks. Given that the degree of craving was not different, we infer that exercise had superior effects to conventional nursing in rehabilitation centers. In addition, the plasma TNF-α levels of the CC and CE groups showed significant differences at week eight, but in contrast, the CE group decreased significantly. This indicates that the effect of exercise on the improvement of plasma TNF-α levels is relatively obvious. The plasma IL-6 levels of the CC group and the CE group both decreased after 8 weeks, but the CE group had more changes than the CC group. This indicates that aerobic combined resistance training has a significant anti-inflammatory effect in individuals with MA withdrawal. The slight decrease in inflammation levels in the CC group may be caused by the environment of the rehabilitation treatment center due to the influence of environmental regulation and the adjustment of self-cognition. This is also an interesting finding of this research. It was found that the level of inflammation in the peripheral system can be improved. At the same time, the blood-brain barrier protects the flow of central inflammatory factors to the periphery.
The change of aerobic combined resistance training on the degree of cue-induced craving under VR exposure
Cue-induced cravings are part of addiction and can easily lead to relapse [29-30]. Exposure to drug-related clues during the withdrawal period can easily cause cravings and lead to relapse [31-33]. VR is a group of seemingly real virtual worlds composed of images and sounds. It is a simulation environment generated by the computer, so that the user is immersed in the environment. It can be delivered to users through visual and auditory senses, making them feel immersive . The immersive nature of VR can be used to modulate various sensory stimuli to evaluate and induce related pathological behaviors and feelings (for example, cravings), and to evaluate possible behavioral responses. The subjects can learn how to better deal with their problems. Park et al. (2019) reported that in addition to addictive psychopathology, VR can also be used for other mental illnesses . Therefore, the VR equipment is widely used in the field of medical treatment and psychological treatment of China's judicial administration drug treatment system, where it is used to diagnose or evaluate the degree of craving, isolate the interference of internal and external environmental factors to a certain extent, and create real experience and feelings for patients. This study also used DDQ as a supplementary scale to supplement VR-VAS evaluation in order to increase its accuracy by incorporating the correlation analysis results of the two scales. The correlation analysis of the three dimensions in VR-VAS and DDQ indicated that the correlation between the two scales was relatively high, and the consistency of internal dimensions was also relatively high. This is similar to the results of the study by Frank et al., (2002) .
Cravings caused by clues can increase blood pressure, heart rate, and skin temperature . This theory is consistent with psychobiological activation. Moreover, grouping is based on the degree of cue-induced cravings, and there are corresponding group differences in blood pressure and heart rate, which also explains the principle of psychobiological activation and the rationality of grouping to some extent. However, it was difficult to screen personnel in the NCC group because the rehabilitation center was isolated from the external environment decreasing accessibility and cravings. This may be because the reason for their drug use is the influence of the surrounding environment, but they cannot get rid of the drug use environment. However, the rehabilitation center plays a role of isolation and insulation at this time. Therefore, after a period of environmental isolation in the NCC group, a smaller heart rate and blood pressure response will occur when the cue is exposed, and this is also related to the individual's sensitivity to the cue exposure. Considering that addiction mental scales are different from objective indicators such as blood, repeated measurements can be taken within a short period of time to enhance the sensitivity and accuracy of the true results of the craving assessment. Therefore, the psychological scales were only collected at two measurement points, at week zero and week eight. The obtained results indicate that there was a certain "ceiling effect" between baseline craving and cue-induced craving in the pre-test, and the VR-VAS score of the NCC group also had a "floor effect" after cue-induced exposure. However, it is undeniable that a consistently high craving score can accurately reflect the "true" high level . According to the severity of cravings in the pre-test of this study, it was found that the CC group and the CE group also showed higher levels of cravings at baseline and after cue-induced exposure.
Previous clinical studies have shown that minocycline, and indomethacin, Ibudilast, and AV1013 anti-inflammatory drugs can reduce the reward effect of methamphetamine on mice, excessive exercise and behavioral sensitization . In addition, minocycline can also reduce self-administration of methamphetamine in rats and relapse of addiction . These drugs are to some extent considered to be drug targets that can treat methamphetamine addiction. Another study reported that short- term aerobic exercise can reduce the cravings of MA addicts and increase their inhibitory capacity . The results obtained in this study also show that aerobic combined resistance training can significantly reduce the cue-induced cravings of methamphetamine withdrawal, and the effect is obvious. This indicates that fighting inflammation and reducing craving through exercise has the same good therapeutic effect as anti-inflammatory drugs.
Exploration of the relationship between plasma IL-1β, TNF-α, and IL-6 levels and the degree of cue-induced craving
Previous studies have confirmed that the inflammation indicators after methamphetamine abuse have significant therapeutic significance. Chronic methamphetamine exposure leads to increased BBB permeability and increases hippocampal IL-1β levels . The level of IL-1β also increased significantly in the analysis of the sample . Abuse of methamphetamine can increase the level of TNF-α in the central nervous system of the brain, and the nucleus accumbens, which is closely related to drug dependence, highly expresses TNF-α mRNA and protein . A previous study reported that deleting the TNF-α gene affects addictive behaviors in wild-type mice, including automatic methamphetamine seeking, motivation to take methamphetamine, and prompting induced cravings and drug-seeking behaviors . IL-6 can participate in neuroinflammatory response  and brain pathological changes , and enter the functional areas of the brain related to various diseases. This indicates that peripheral inflammatory factors are closely related to central nervous system damage and drug seeking.
This study showed that the plasma inflammation levels in the CC group and the CE group were similar. Interestingly, when the craving degree is significantly different between the NCC group and the CC group, the plasma inflammation level is also different. In addition, the correlation analysis between the predicted VR-VAS score and the plasma inflammation level shows that they are both positively correlated. This indicates that plasma inflammation levels in methamphetamine withdrawal patients are significantly related to drug cravings caused by brain inflammation. This may be similar to the results of previous studies on the damage of peripheral and central nervous system structures and mental disorders.