The mechanisms proposed so far for the action of opium on the three above biochemical factors are summarized in Figure 1. Short term effects are mostly exerted via hormonal and neural mechanisms, but long term effects are often due to the structural and functional alterations. In long term, depending on consumption dose and duration and other factors, different mechanisms are gradually involved. As it was mentioned before, acute hyperglycemic effects of morphine were mediated through CNS, leading to glycogenolysis and decrease of insulin release (Molina et al., 1994). This response is exaggerated in diabetic states that have been attributed to the increase of glucagon secretion (Ipp et al., 1980). In addition, insulin resistance with opiate use may be coupled with β-cell dysfunction. It has been shown that in response to an intravenous glucose load, opiate addicts had a 42% lower insulin response, accompanied by an 80% lower glucose reduction rate than non-addicted subjects (Ceriello et al., 1987). Moreover, increased fasting insulin levels in addicted subjects were also observed. In addition elevation of glucose utilization and the reduction of hepatic gluconeogenesis subsequent to the activation of peripheral opioid μ-receptors and the modification of genes involved in glucose metabolism (Liu and Cheng, 2011) are among suggested mechanisms. The reduction of 2-h post prandial glucose (2HPP) in diabetic addicted individuals (Azod et al., 2008) might be due to the decrease of gastric emptying due to opioid μ-receptor activation and thereafter delaying the intestinal glucose absorption. Moreover, the presence of underlying diseases and probable effects of medicines taken by the subjects may also come into play. In some reports despite normal glucose levels in opium addicts, there were hyperinsulinemia along with altered glucose metabolism similar to what occurs in type 2 diabetes (Sheldon and Quin, 2005). In animals however, the mechanisms such as increment of adrenalin, noradrenaline, cortisol, glucagon, etc., have been involved in increasing blood glucose (Radosevich et al., 1984). The lower FBS reported in some studies in addicted individuals has been ascribed to the anorexia secondary to opium use that cause decrease in body mass index (BMI) and insulin resistance.

Regarding the effect on blood pressure, morphine is a vasodilator in human although not through opioid receptors (OPRs), but through histamine-modulation of nitric oxide (NO) release (Headrick et al., 2012). This response is also dysregulated in diabetes (Afshari et al., 2009). Kappa-OPR agonist mediated reduction in systolic pressure has also been reported to be reduced in chronic hypertension (Bolte et al., 2009). This seems to be OPR- and K+ channel-independent, and it is less dependent upon L-type Ca++ channel function (Guo et al., 2007). Overall, it seems that the effect of opium on blood pressure is related to the dose and duration of drug consumption. Low dose and short term opium administration often decreases blood pressure and the effect is exerted via vasodilatation and reduction of sympathetic tone. In long term, the effect of opium on the reduction of blood pressure is reduced and a trend of increase in blood pressure supervenes (Joukar et al., 2010). The increase of plasma homocysteine and fibrinogen (Masoomi et al., 2002, 2015; de Luis et al., 2005) that predisposes the addicted persons to a higher risk of blood clotting, atheroma formation and resultant vascular narrowing may involve in long term effects. Homocysteine by itself is a risk factor for developing atherosclerosis and pathological changes in vascular function, especially in diabetes (de Luis et al., 2005). Overall, it is concluded that opium not only has no ameliorating effect on hypertension, but also it is a risk factor for cardiovascular diseases.

Regarding the mechanism of the effect of opium on blood lipids, some probable mechanisms proposed are reduction of hepatic clearance of LDL cholesterol from the plasma and augmenting hepatic synthesis of triglycerides, leading to the elevated levels of total cholesterol (TC) and triglycerides (TG), respectively (Bryant et al., 1988). Since lipids can penetrate blood brain barrier, they may have a role in the CNS associated with drug addiction (Hillard, 2005). However, it is not clear whether the lower level of TC (Divsalar et al., 2010; Mohammadi et al., 2013) and TG (Hosseini et al., 2011; Rezvanfar et al., 2011) in opium addicts reported in some studies are result of opium consumption or they are cause for opium addiction. Some of the authors attributed these to the lower BMI in the opium addicts. Gozashti et al. showed that TC and HDL significantly decreased in opium addicts, but TG remained unchanged (Gozashti et al., 2015). In this regards, feeding hypercholesterolaemic rabbits with opium caused an increase in the levels of TC, TG, and LDL cholesterol whereas these variables decreased in normocholestrolaemic rabbits (Mohammadi et al., 2009). In another study by the authors on hypercholesterolaemic rabbits that were exposed to opium smoke, a fall in HDL-cholesterol was found with no significant effect on the other lipids (Najafipour et al., 2010). Therefore, the route of opium consumption (enteral vs. inhalation) might have affected the impact of opium on lipid profile. In human studies, in a recent population-based study, opium use had no significant association with abnormal level of HDL and TG (Yousefzadeh et al., 2015).

Overall the results of animal studies may be more consistent and reliable because in clinical studies, some conditions may be different between addicts and non-addicts that may affect the results. Some of these factors include:

1. Nutritional factors: Many addicts lost their jobs and had to pay extra expenses to provide their required substance. This led opium users to suffer from malnutrition and vitamin deficiency. Also, the use of opiates suppresses appetite and reduces weight in many instances (Divsalar et al., 2010). Therefore, the reduction of lipids in some studies might be due to weight loss or nutrient deficiency not owing to direct effect of opium.
2. Individual factors such as underlying diseases, psycho-social problems, physical activity level, and age range of subjects may alter the effect of opium on serum lipids. Also these conditions may alter serum biochemical variables independent of the effect of opium.
3. Factors relevant to the substance including purity and ingredients of opium, concomitant use of other substances (alcohol, cigarette, tobacco,…), duration, quantity and method of usage. Opioids have negative impact on many organs such as liver. Opioids are mainly metabolized in the liver, hence chronic consumption of the substance leads to serious liver damage. It has been demonstrated that chronic administration of morphine causes the suppression of hepatic antioxidant system, elevation of oxidant indices and induction of apoptosis in hepatocytes in mice (Zhang et al., 2004; Payabvash et al., 2006). It has also been shown that there is a direct association between the duration of heroin consumption and the severity of liver injury in heroin abusers (Zhang et al., 2004; Ilić et al., 2005). Since liver plays a pivotal role in the metabolism of lipids, chronic liver diseases are associated with significant alterations in serum lipids (Ooi et al., 2005; Ghadir et al., 2010).
4. The factors relevant to research: Many human studies have small sample sizes or are hospital-based instead of population-based. Therefore, the results may not be generalized to the whole population.

Although a large body of evidences is available from human studies regarding the impact of opium consumption on cardio-metabolic disorders, however most of these studies are cross sectional in their design. Limitations of the cross-sectional studies are simultaneous data collection concerning risk factors and outcomes which prevents an exact examination of the temporal transposition between them. In other words, it cannot be said for sure whether the higher prevalence of disorders in opium users is the result of opium consumption or the cause for opium consumption. Therefore, it is suggested that more prospective longitudinal studies with large sample sizes to be conducted to clear this temporal precedence and to identify the pathophysiological mechanisms more precisely.