This study aimed to evaluate the association between opium use and TH levels (T3, T4, and TSH). The findings showed that T3 and T4 levels decreased in opium users, which might suggest hypothyroidism. On the other hand, opium use was associated with higher TSH levels. Overall, it is speculated that opium use is associated with primary hypothyroidism.
Some studies have shown that alcohol, cocaine, and heroin addiction have no significant effects on the secretion of pituitary hormones and possibly, T3 and T4 levels. However, others have indicated changes in T3 and T4 levels, mostly due to the direct effects of these substances on the thyroid gland [25, 26]. A study by Dogar et al. reported controversial results regarding the inhibitory effects of opium on TH levels. This observation showed that addicts had higher T3 levels compared to healthy individuals [27]. Rasheed et al. also found that heroin abuse increased T3 levels compared to the control group. Additionally, the level of T4 was not significantly different between addict and non-addict groups [15].
In another study by Brambilla et al., the results showed that addictive substances had no effects on T3 and T4 levels [28]. Although some studies have emphasized the effects of these addictive substances on lowering THs, some studies show no TSH-lowering effects. It should be noted that differences in sample size, type of addictive substances, and studied populations might result in these controversies. Nonetheless, it can be concluded that these substances have some suppressive or destructive effects on the pituitary gland, which are associated with secondary hypothyroidism pathogenesis.
The hypothalamic-pituitary-thyroid axis is a continuous longitudinal pathway, which involves several biological mechanisms. Negative feedback increases the level of TSH, followed by a reduction in T4 and T3 levels [29]. The present study revealed that opium simultaneously suppressed the thyroid gland function and induced the activity of pituitary hormones. Theoretically, it can be concluded that opium use is associated with hypothyroidism (probably primary hypothyroidism), which is followed by a rise in TSH levels. In a study by Gozashti et al., comparing the thyroid function of 50 addict and 50 non-addict participants, similar findings were reported, although our study concentrated on the distribution of THs that influenced the reliability of results [23]. Basically, THs are not normally distributed, even in large sample sizes [30]. Therefore, it is important to apply nonparametric tests to investigate different aspects of THs.
The present study showed that TSH, T3, and T4 levels had a significant non-normal distribution. Consequently, Mann-Whitney U test was applied to compare the levels of these hormones between opium users and non-users. Nonetheless, normal distribution is an important assumption in linear regressions; therefore, we could not perform this analysis. In the current study, the participants were divided into low, normal, and high hormone levels, based on the normal range of each hormone. Next, multinomial regression analysis was performed to investigate the risk of each pathological condition in opium users. Finally, our findings supported that opium users had a significantly higher chance of lower T4 and T3 levels and higher TSH.
The results of studies by Zhang et al. [31] and Bhoir et al. [32] are consistent with ours. Although the correlation of opium use with hypothyroidism was significant in some previous studies, no significant difference was found relative to the control group. According to previous observations, lower TH levels are correlated with the level of thyroxine-binding globulin (TBG) in the liver tissue. Generally, the T3 resin uptake (T3RU) assay is the most commonly applied tool for determining TBG levels [33]. Accordingly, the overall profile of T3 and T4 hormones should be evaluated to make more accurate inferences from the results.
A study by Shenkman et al. reported that TSH levels were normal in addicts compared to the control group [34]. Also, Brambilla et al. showed that heroin abuse did not affect TSH levels [28]. Some studies have not examined TSH levels alongside other hormones [27]. In line with the present study, Pende et al. documented increased TSH levels following buprenorphine and heroin abuse [35].
Different theories have hypothesized the downregulation of T4 and T3 in opium users. Since our results suggest the significant risk of primary hypothyroidism, opium use can induce cellular death or suppression in the thyroid glands. A review study by Mirzaei et al. emphasized that opium and its derivatives induce apoptosis in different cells, especially in the liver, brain, and immune system [36]. Remarkably, opium upregulated both extrinsic and intrinsic pathways of apoptosis through activation of caspase 9, caspase 8, and caspase 3 [37–39]. The probable destructive effects of chronic opium abuse on thyroid cells should be investigated in future studies.
The present study had some limitations. Regarding the common characteristics of cross-sectional studies, our findings showed no cause-and-effect association between opium use and TH levels. On the other hand, for legal and ethical reasons, it was not possible to conduct interventional studies to determine the effect of opium on thyroid function; therefore, further retrospective and prospective cohort studies are required to overcome this limitation. Besides, there are still some controversies about TSH levels in opium users. The current findings support the possibility of primary hypothyroidism and the indirect effect of opium use on the pituitary gland, based on negative feedback. Nevertheless, further studies are required to investigate the molecular and cellular mechanisms of this condition.
The present study had several strengths. First, the large sample size of the Persian Cohort of Fasa, which was used in the present study for the first time, provided some new information. Second, our clinical approach of dividing the participants into low, normal, and high levels of each hormone provided more reliable results. Third, the patients were classified into different categories of thyroid function, and their findings were compared with those of a normal population (separately for each hormone). However, future studies with a larger sample size are required to investigate the odds ratio of each pathological condition in opium users.