Drug addiction can simultaneously destroy the ventral tegmental area-nucleus accumbens reward circuit, prefrontal cortex-related executive control circuit, paraventricular nucleus of the thalamus-related circuit, etc. [6]. It causes abnormal reward system, decline of inhibition control function, distortion of motivation system and solidification of memory circuit [7][8]. Liu et al. [9] 137 imaging studies uniformly verify that chronic methamphetamine addicts have atrophy of gray matter in nucleus accumbens, decrease of blood flow in dorsolateral prefrontal cortex and disorder of functional connectivity of whole brain. Therefore, the key reason why drug addiction is difficult to cure lies in pathological changes in neural circuits, in which the formation and extraction mechanism of addictive memories is the key neurobiological basis for driving substance use behavior or relapse of addictive symptoms [10]-[12]. At present, many studies have revealed the mechanism of pathological damage to neural circuits, but the specific mechanism of action and the dynamic changes in the process of drug addiction are not yet clear. In addition, the essence of drug addiction is the occurrence of organic pathological changes in the multi-brain region collaboration network, single body detoxification cannot reverse brain circuit damage, which is also the key reason for the high long-term relapse rate of drug detoxification alone [13].

Dopamine plays an important role in all stages of drug addiction [14] and can enhance drug-seeking behavior by continuously activating the mesolimbic reward circuit [15]. Saunders et al. [16] found that conditioned responses occur only under stimulation of the ventral tegmental area of the midbrain, proving that midbrain dopamine neurons are crucial. In addition, all kinds of addictive drugs will eventually directly or indirectly increase the concentration of dopamine in synaptic cleft [17]. After long-term stimulation, the body compensates for downregulation of dopamine D2 receptor quantity and sensitivity [18]. Volkow et al. [19] confirmed through positron emission tomography (PET) imaging that the concentration of D2 receptor in heroin addicts’ brain decreased by 35%-50% compared with healthy people. The lower the receptor level, the more obvious the compulsive drug-seeking behavior of patients. Trifilieff et al. [20] further indicated that PET imaging consistently demonstrates blunted striatal dopamine release and diminished D2 receptor availability in addiction, which represent both a consequence of chronic drug use and a susceptibility factor for the development of addiction. Hypothalamus-pituitary-adrenal axis (HPA) is the main stress regulation endocrine pathway of the body. When patients are in a long-term drug abuse or compulsory detoxification state, they will face strong psychological and physiological double stress, thus activating HPA and making cortisol (COR) concentration continuously high [21]. Nikbakhtzadeh et al. [22] also indicated in their review that stress constitutes a significant risk factor for the development of addiction and relapse vulnerability, and that post-stress alterations in the HPA axis directly influence reward-related brain regions, including the ventral tegmental area and nucleus accumbens. Studies have shown that a sharp rise in COR is closely related to anxiety, depression, cognitive impairment and other stress symptoms, which are important drivers of drug craving [23]. In addition, abnormality of serotonin (5-HT) level is an important sign of withdrawal reaction and relapse impulse, “activation of HPA system-COR mediated-increase of 5-HT level” is an important pathway to induce drug craving and relapse, and reducing 5-HT secretion can block drug-induced relapse behavior [24]. Ciccocioppo [25] noted in his review that the 5-HT system serves a core function in impulse control, and that serotonergic deficits may result in impaired regulation of drug consumption, constituting a key determinant in the persistence of addictive behaviors. Glutamate participates in the encoding and consolidation of long-term memory through synaptic plasticity mediated by the activation of N-methyl-D-aspartate (NMDA) receptors [26][27]. Addictive memory is abnormally persistent in the brain and constitutes an important neural basis for the long-term relapse risk after detoxification [28]. A transgenic mouse study [29] demonstrated that selective knockout of the NR1 subunit of NMDA receptors on dopamine D1 receptor-expressing neurons completely abolished the acquisition of conditioned place preference for cocaine-, morphine-, or ethanol-paired contexts, while leaving memory for sucrose reward and naloxone-induced aversion intact. This indicates that NMDA receptor-dependent neural plasticity is necessary for drug-associated contextual memory, but not for general reward learning.

On the basis of brain physiological damage, drug addicts will form abnormal cognitive patterns and behavioral habits, which belong to the external manifestation of addiction at psychological level. First, attention will unconsciously give priority to drug-related stimuli; secondly, cognitive level will underestimate the risk of illegal activities and health damage; finally, classical conditioned reflex will be established, and environmental incentives will directly trigger drug-seeking impulse. A large number of studies have shown that belief in self-abstinence is the key to preventing relapse, and self-awareness is the foundation of long-term stages [30]. Cognitive distortions and addictive behaviors are the process of addiction from organic diseases to external bad behavior patterns, and are also the main focus of psychological non-pharmacological interventions.

Psychobehavioral intervention is a psychological treatment aimed at the cognitive, emotional and behavioral problems of addicts. It can reduce drug craving and prevent review by reshaping cognitive patterns and regulating intrinsic motivation, among other approaches. It mainly includes mindfulness intervention, cognitive behavioral therapy and motivation interview. Mindfulness-based relapse prevention (MBRP) can help drug addicts strengthen their belief in detoxification. Liu et al. [31] conducted a randomized controlled trial involving 58 young female methamphetamine dependents from Sichuan Province. The MBRP group (n = 29) received 4 weeks of MBRP training, while the control group (n = 29) received only routine treatment. The results showed that the MBRP group exhibited a significant reduction in the total score of the Obsessive Compulsive Drug Use Scale (OCDUS) from baseline (33.41 ± 8.17 vs. 29.83 ± 6.94, P < 0.01), and a significant increase in the total score of the Five-Factor Mindfulness Questionnaire (FFMQ) (117.45 ± 16.84 vs. 122.76 ± 15.36). These findings indicate that MBRP training can effectively enhance trait mindfulness and reduce psychological craving in methamphetamine-dependent individuals. Cognitive behavioral therapy helps addicts correctly deal with high-risk situations and negative emotions by changing their bad cognitive and behavioral patterns of drugs. Aslan et al. [32] conducted an 8-week nurse-led randomized controlled trial of cognitive-behavioral therapy involving 72 incarcerated males with methamphetamine use disorder in Türkiye. The intervention group received eight sessions covering cognitive restructuring, craving management, stress coping, and relapse prevention, while the control group received treatment as usual. The results showed that the intervention group exhibited a 38.5% reduction in craving intensity from baseline and a 26.7% improvement in overall stress coping strategies. All three coping domains showed significant improvements: social support seeking increased by 34.1%, problem-focused coping by 16.1%, and adaptive avoidance by 33.7%. In terms of effect sizes, stress coping demonstrated a large effect, while craving reduction showed a medium effect. The core purpose of motivational interviewing is to explore and resolve the ambivalence of individual behavior, and to promote behavior change by arousing the motivation for change in the addict’s ambivalence. Polcin et al. [33] conducted a randomized clinical trial involving 217 methamphetamine-dependent individuals, in which participants were randomly assigned to either a 9-session intensive motivational interviewing group (IMI) or a single session of standard motivational interviewing combined with eight nutrition education sessions (SMI). The intervention was delivered weekly over 8 weeks, and all participants concurrently received standard outpatient group therapy three times per week. The results showed that both groups demonstrated significant improvements in the percentage of days abstinent from methamphetamine use (from baseline to follow-up) and in the drug composite scores of the Addiction Severity Index, with no significant differences between the two groups. However, the IMI group showed significantly greater improvements than the SMI group in the psychiatric composite scores of the ASI and in the number of days experiencing psychiatric problems over the past 30 days. These findings suggest that motivational interviewing can reduce drug use by enhancing intrinsic motivation for change among addicted individuals, but increasing intervention intensity may not confer additional benefits on drug use reduction itself, whereas greater intensity may be required for improving comorbid psychiatric symptoms.

Exercise intervention is a non-invasive intervention method to relieve withdrawal physical discomfort, relieve drug craving, improve negative emotions, improve physical fitness and comprehensively promote physical and mental health of addicts through planned and standardized various types of somatic movement training. In drug addiction treatment, the commonly used exercise interventions mainly include aerobic exercise, psychosomatic exercise, high intensity intermittent training and resistance training. Aerobic exercise improves cardiorespiratory function and mental health mainly through sustained exercise of moderate intensity. Lyu et al. [34] studied the effect of acute aerobic exercise on craving and risk decision-making in methamphetamine use disorder (MUD) patients. 30 male MUD participants were recruited for randomized controlled experiment. The results showed that acute aerobic exercise can effectively reduce craving and enhance decision-making performance, especially in the field of impulsive and short-sighted decision-making. However, the present study is limited in its ability to establish correlations between a single experimental session and long-term benefits, as well as associations with gender. In another study, Tang et al. [35] randomly divided 100 MUD patients into 12-week control group, in which the experimental group received moderate-to-vigorous aerobic exercise (MVE) intervention and the control group received low-to-moderate-intensity exercise intervention. It was found that MVE helped to relieve negative emotions and reduce drug craving. Physical and mental exercise could also reduce drug craving and improve physical fitness of drug addicts. Zhang et al. [36] conducted a randomized controlled trial in which 48 men with methamphetamine use disorder were randomly divided into Tai Chi group and running group, and were intervened 3 times a week for 12 weeks. It was found that Tai Chi improved the patients’ attention and reaction ability compared with running. High intensity interval training involves alternating short bursts of high intensity exercise with intermittent recovery periods, demonstrating significant efficacy in reducing drug craving in individuals with substance addiction. He et al. [37] conducted a randomized controlled experiment on 40 methamphetamine dependent men and found that long-term high intensity intermittent training increased the activation of ventrolateral prefrontal cortex in MUD men and reduced drug craving. Resistance training enhanced muscle strength and endurance by resisting resistance, often in the form of equipment exercise, elastic band, weight training, etc. Nygard et al. [38] conducted a randomized controlled trial of 40 subjects three times a week for 12 weeks and found that maximum strength training improved bone and muscle health.

physical-neuromodulation intervention is a kind of non-invasive physical rehabilitation method, which can reduce drug craving, improve cognition and regulate emotion of drug addicts by acting on addiction related brain areas through external conduction. The two commonly used neurophysiological modulation interventions in the field of addiction treatment are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation. A randomized controlled trial conducted by Wang et al. [39] divided 64 methamphetamine dependents into sham stimulation control group and high frequency repetitive transcranial magnetic stimulation (HF-rTMS) intervention group. The final study found that HF-rTMS could alleviate drug craving and improve cognitive decision-making ability of subjects. Wang et al. [40] further found that HF-rTMS combined with physical exercise can further optimize the subject’s mood and reduce drug craving. Transcranial direct current stimulation regulates cortical excitability by applying weak direct current to the scalp, thus reducing drug craving and improving cognitive function in drug addicts. Borzooee et al. [41] found that transcranial direct current stimulation reduced craving and improved executive function in opioid addicts in a randomized controlled trial. Ahmed et al. [42] conducted a double-blind randomized controlled trial involving 40 male patients with opioid dependence in India. Craving and psychosocial functioning were assessed using the Obsessive-Compulsive Drug Use Scale and the Addiction Severity Index at baseline, immediately post-treatment, and at 2- and 4-week follow-ups. At baseline, no significant differences in OCDUS scores were observed between the two groups. Following treatment, the Active group showed significantly greater reductions in craving than the Sham group at Day 5 and Day 14, with the effects maintained at Day 28 [42]. This study further confirmed that five sessions of right dorsolateral prefrontal cortex transcranial direct current stimulation can produce rapid, significant, and sustained reductions in opioid craving.

Besides psychobehavioral intervention, exercise intervention and physical-neuromodulation intervention, acupuncture and external treatment of traditional Chinese medicine, digital therapy and family intervention also play an important role in drug addiction rehabilitation. Clinical studies by Wu et al. [43] found that acupuncture has the advantages of treating withdrawal syndrome and has the potential to prevent relapse. Shen et al. [44] conducted a three-arm randomized controlled experiment on methamphetamine dependents from 12 communities in Sichuan Province, China, and found that gamified adaptive method bias correction can reduce participants’ drug craving. Sarani Yaztappeh et al. [45] conducted a randomized clinical trial for high-risk adolescents, dividing 60 adolescents into selective defense group, family-based defense group and control group. The results showed that family intervention plays an important role in preventing substance abuse. Robbins et al. [46] showed that compared with conventional therapy, family therapy has advantages in reducing drug use and maintaining family member participation in treatment.