Social anxiety disorder (SAD) is mainly caused by a combination of environmental and genetic factors. SAD is characterized by discomfort in various social contexts, such as public speaking, interaction with visitors, or dealing with strangers. Studies report higher incidence of SAD in women relative to men (1–3). People with severe SAD exhibit various physical reactions such as headaches, cold sweats, and gastrointestinal discomfort, which may lead to social avoidance (4). In addition, severe SAD can lead to substance use disorders (SUD) (5). A previous study reported that SAD affects the rate of relapse among drug addicts to some extent. Individuals with SAD have a high risk of developing SUD (6). The study reports that patients with SAD have a two-fold risk of using heroin compared with subjects without SAD (7). SAD is common among patients seeking SUD treatment. A previous study reported that a quarter of patients seeking opiate dependence treatment exhibited SAD (8). In addition, a study reported patients who received pharmacotherapy for opiate dependence had higher SAD levels compared with controls (9). Moreover, findings indicate that half of substance dependence patients have clinically elevated SAD (10). Studies indicate that heroin dependence is associated with social avoidance during withdrawal owing to the high level of physical dependence and emotional disorders (11).

OT is a neuropeptide that is released into the bloodstream from the posterior pituitary and it exhibits several central and peripheral blood effects (12). In addition, OT regulates several aspects of social cognition, social behaviors, and fear conditioning. These effects result in SAD and other disorders associated with impaired social functioning (13). OT levels are high in females relative to the level in males (14). Notably, OT protects females from SAD. Hoge reported low plasma OT levels in patients with a generalized SAD during a pro-social laboratory task paradigm (15). A study by Meyer-Lindenberg indicated that increased levels of OT may prevent SAD (16).

Moreover, OT plays a vital role in establishing clinical experimental models of addiction, relapse, and craving. Studies report that daily peripheral blood OT administration lowers self-administration of heroin in heroin-tolerant rats (17). In addition, OT can attenuate craving and alleviate withdrawal symptoms in female heroin-dependent patients; thus, it is a potential therapy for heroin dependence (18). Furthermore, OT decreases stress and cued reinstatement of opioid seeking (19). OT improves multiple aspects of social functioning, including emotion recognition (20) as well as social abilities in patients with opioid use disorder. These effects ultimately promotes engagement of the patients in psychosocial treatments and social support systems (21).

Regular aerobic exercise increases the plasma OT level in female mice, reduces anxiety, and increases emotions (22). Jazaieri reported that aerobic exercise can improve SAD (23). Effect of exercise on drug addiction and relapse process has been extensively studied and studies report that Qigong can prevent heroin detoxification without side effects (24). In addition, a significant association was observed between exercise and substance abuse in women compared with men (25). SAD and heroin dependence are correlated with OT levels.

The aim of the current study was to explore whether the degree of SAD in heroin withdrawal subjects was correlated with the level of peripheral blood OT. Moreover, the effect of exercise on peripheral blood OT levels, SAD levels, and cue-induced cravings in heroin withdrawal subjects was explored.

Participants under drug rehabilitation programs present with high number of drug-dependency complications compared with their counterparts. Previous studies report that SUD is significantly associated with SAD. Patients presenting with both SAD and SUD show severe complications compared with subjects with only a single disorder. Therefore, treatment of patients with SAD–AUD complications should not be limited to only a single disorder. Identification of possible similarities between the two treatments can provide a new therapeutic target for SAD–AUD patients. Correlation analysis based on LSAS, VAS, and DDQ scores shows a positive correlation between severity of SAD, VAS-craving, and “Desire and Intention,” indicating an interactive relationship between SAD and AUD. However, the results of the present study showed no correlation between “Negative reinforcement” and “Control” according to LSAS scores. This can be attributed to the small sample size used for the study or the high number of dropouts in this study. The findings showed significant differences in VAS-craving between the SAD group and the Non-SAD group. This implies that heroin addicts with SAD show high levels of fear during social interaction and social attachment. In addition, heroin addicts feel more inferior and nervous in social settings. Therefore, their inner loneliness increases, positive emotions decrease, and present with physiological arousal. These subjects thus rely on other ways to compensate for their inner positive emotions. Moreover, heroin addicts have the urge to compensate for their inner positive emotions when subjected to drug simulation cues. The pathological memory thus overlaps with physiological arousal and drug craving increases.

Studies report a positive association between OT and anxiety symptoms. For instance, a study comprising 29 patients with obsessive–compulsive disorder reported a higher OT level associated with more anxiety symptoms (34). Moreover, plasma OT level is positively correlated with anxiety composite scores in healthy women (35). On the contrary, Scantamburlo et al. (36) reported a negative correlation between anxiety symptoms and OT level in a group of 25 depressed patients. The findings of the present study exhibited a significantly high negative correlation between plasma OT levels and severity of SAD, which was consistent with the findings by Scantamburlo et al. (36). The severity of SAD and the baseline plasma OT levels were significantly different between SAD patients and Non-SAD patients. However, severity of SAD and the baseline plasma OT levels between the SAD control group and the SAD exercise group were not significantly different. This verified the correlation analysis results. Woolley et al. (21) conducted a study on the correlation between OT and heroin cue-induced cravings and reported that intranasal administration of a single OT dose to opioid users undergoing opioid replacement therapy was well-tolerated without significant effects on craving. This finding indicates a significant association between OT levels and heroin cues. Nikolaou et al. (37) reported a positive correlation between plasma OT levels of participants and scores based on COWS, VAS-Craving, and the Hamilton Anxiety scales. Contrary to these findings, Lin et al. (38) reported a negative correlation between plasma OT levels and craving levels in female heroin-dependent patients under methadone maintenance. The negative correlation was most significant in subjects with lower scores of novelty-seeking behaviors. VAS and DDQ scales were used in the present study to explore the relationship between cue-induced craving and plasma OT levels. The results showed that VAS-craving, “Desire and Intention,” and “Negative reinforcement” scores exhibited a negative relationship with plasma OT levels. Notably, VAS assessment results showed significant correlation with OT levels compared with the relationship between “Desire and Intention” and OT levels. VAS has fewer dimensions and short time; thus, it is easy to directly reflect a relationship. Moreover, the finding indicates that the DDQ scale is used to complement VAS in determining the degree of desire. A consistent negative correlation using both DDQ scale and VAS scale indicates the relationship between plasma OT levels and cue-induced cravings.

The results showed that aerobic combined with resistance exercise for a period of 8 weeks increased plasma OT levels of heroin withdrawal and alleviated SAD and cue-induced cravings. The efficacy of AE can be explained by the fact that aerobic exercise mimics the same bodily sensations elicited by anxiety reactions, such as increased heart rate, respiration, and perspiration (39). Therefore, exercise prompted the participants to differently evaluate their bodily responses (such as in a less threatening manner) compared with when they are not going through exercise training. In addition, repeated exposure to social stimuli at the gym could have caused habituation to social fear and changes in social cognitions, thus helping in alleviation of SAD symptoms. This indicates that exercising in an anxious situation results in alleviation of anxiety symptoms (39). Moreover, exercising (improving one's physical health) can induce decrease of negative judgments and enhance kindness toward oneself (self-compassion). A previous study reported that exercise can improve anxiety through repeated exposure, improved self-efficacy, and distraction (40). A randomized controlled trial conducted to improve SAD reported that first-time use of aerobic exercise and group lessons for 8 weeks effectively alleviated severity of SAD. Similarly, findings from a previous animal study showed that aerobic exercise increased OT levels in female mice, alleviated anxiety, and increased empathy. Aerobic exercise combined with resistance exercise is an effective alternative to improve physical health and reduce cravings of drug-dependent people. Furthermore, aerobics combined with resistance training can significantly alleviate anxiety and depression associated with drug dependency (41). Moreover, it can improve aerobic exercise performance, muscle strength, and endurance, and promote recovery from drug dependence (42).

The present study had several limitations. For instance, the sample size was too small, and most of the participants withdrew from the study. The study sought to recruit and screen more subjects. However, in order to control the rigor of the research during the screening process, a population of 1,026 people were screened based on the standard of “heroin only;” thus, only one-third of the subjects were eligible. This resulted in inclusion of a smaller number of subjects in the study. Furthermore, the effect of the female menstrual cycle was not explored despite its potential effect on plasma OT levels (43–45). Peripheral blood OT level was determined in this study and not the central nervous system level. Previous animal studies report that the peripheral and central nervous systems are coordinated. Furthermore, plasma osmolality was not evaluated, which may affect plasma OT levels. DDQ and VAS scales were used to explore the craving degree to ensure the findings were accurate. However, this study lacks objectivity, owing to lack of objective indicators for strong demonstration. Although the preliminary experiments explored the clues that induce changes in blood pressure and heart rate during craving, these findings are not included in the study.

Although the relationship between OT level and SAD and heroin addiction has been extensively studied, only a few studies have explored the relationship between endogenous OT and the interaction between SAD and heroin addiction. Therefore, this is the first study to explore the effect of exercise in heroin addicts with SAD. The findings of this study indicate that adjuvant therapy, such as exercise, can improve the level of endogenous OT in drug withdrawal patients with SAD.

Plasma OT is a potential peripheral biomarker for prediction of severity of social anxiety in female heroin withdrawal Patients. Moreover, exercise can be used as an adjuvant therapy to increase the level of OT in heroin withdrawal patients and alleviate SAD and cue-induced craving.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Institutional Review Committee of Hunan Normal University approved. The patients/participants provided their written informed consent to participate in this study.

JW, JZ, LZ, and YG conceived and designed the experiments. JT, TH, and JL screened experimental subjects, signed the informed consent process, and conducted the exercise intervention. All authors contributed to the article and approved the submitted version.

The authors declare that this study received funding from the National Key Research and Development Program of China (Grant No. 2016YFC0800908), the Research and Innovation Program for Postgraduates of Physical Education College of Hunan Normal University (TYCX2019B007), the Scientific Research Project of Hunan Provincial Department of Education (19C1133), the Philosophy and Social Science Fund Project of Hunan Province (18YBQ088), and the China Postdoctoral Science Foundation Funded Project (2017M622580). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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