1. Introduction
1.1. Civilization and Testosterone
According to Lamarck's theory of evolution (1), animals respond to their emerging needs by exhibiting adaptive reactions. This endeavor changed their habits and functions and was further conveyed to animals’ offspring and ensuing generations (2). Later, Darwin presented the natural selection theory (3). Darwin’s theory, in contrast, addressed the influence of factors other than natural selection such as inheritance, gene mutation, and the environment (4). In both models, however, reproduction is a key element to preserve life (5). Evolution, therefore, is considered as a process of change in living organisms with the ultimate goal of preserving life and survival by adapting to the environment (6).
Reproduction is an adaptive process to generate new genetic variations and fresh and isolated organisms (7). However, reproduction requires liaison and integrated synergism of biological (internal) and non-biological (external) agents such as cells, hormones, paracrine factors, genes, epigenetic regulators, nutritional conditions, photoperiod, pheromones, and stress (8). The interactions among thousands of genes, the epigenetic control of gene expression, and environmental and lifestyle factors affecting genetic and epigenetic variants determines the resulting reproduction (9). Seasons, as an external factor, create distinct patterns for numerous natural processes and evolutionary adaptations, including mating rhythms (10). The climax of mating and reproduction behavior in many animals is confined to specific season(s) or years when their steroid cycle activity and sperm production are maximal (11).
Testosterone, a product of Leydig cells, is a key hormone in reproduction, and an appropriate level of which is required in the bloodstream for effective reproduction (12). A higher level of testosterone, however, is not necessarily beneficial and can even impede survival. For example, high-level testosterone in the youth increases the suicide risk (13). Testosterone has also been suspected as a risk factor in developing mental disorders such as schizophrenia (14). Suicidal thoughts in patients with positive symptom schizophrenia are also higher (15), which may reflected the augmented effect of testosterone. Accordingly, an optimal window effect of testosterone is likely for survival, and this effect is reversed in higher and lower levels. In other words, an agent (i.e., biology) may shield survival and evolution at one level and endanger survival at another level (i.e., social level).
Convincing evidence indicate the higher levels of testosterone in early humans (16). The gradual diminution in androgenic hair is the phenotypical evidence of lowered testosterone levels in humans (17). The decline of testosterone, however, appears to precede the evolution of civilized humans (16). It also makes human males be less aggressive, less isolated, and less competitive; hence, they become more sociable, interactive, and stable in their relationships (18). Those changes seem to be prerequisites to civilization (19). In other words, the lower levels of testosterone and human civilization appear to be an intertwined evolutionary process. Although researchers have documented that human testosterone decline is still in progress (20), to the best of our knowledge, there is no clear explanation on how this decline is happening. Following the suppression of testosterone, however, early humans became self-domesticated and prosocial, began living in families, and became creative (21).
1.2. Opium Poppy and Testosterone
Previous studies have suggested that the opium plant acquired its poisonous property (22) to be avoided as an alimentary source for herbivores and, therefore, to secure its survival under hostile environmental conditions (22). However, some animals, including humans, evolved to benefit the useful properties (e.g., painkilling effects) of opium poppy and other alkaloid producing plants without being beaten by their fatal attributes (23). The painkilling and anti-inflammatory effects of opium (24) helped ancient humans tolerate trauma-related pain, thereby securing their survival (25). With their somniferous properties and the induction of pleasant feelings, opiates have been consumed by mankind throughout history (26).
According to Hamilton's rule, for a specific behavior to continue in a particular group or species, the advantage of practicing that behavior should outweigh its disadvantages (27). Opiate consumption may be associated with a wide range of side effects, including constipation (28), sleep disorders (29), respiratory depression (30), cardiovascular system effects (31), increased risk of bone fracture due to drug-induced falls (32), immune system suppression (33), and decreased testosterone level (34). In this regard, from an evolutionary perspective, the continued consumption of opium (35), despite their adverse effects, arouses the assumption indicating that the benefits of opium to humans outweigh such side-effects. In line with this assumption, the ceremonial rituals of opium use (36) further documents its superior benefits for humans. Opium has been used not only for medication but also for ceremonies as such the Sumerians called it the plant of Joy (37). Accordingly, one can postulate that male humans primarily used opiates for their painkilling and other positive effects; however, they were subsequently influenced by their testosterone-reducing effect.
Moreover, the evolutionary process of testosterone decline in humans seems to be mediated by narcotics, where a potentially counter-revolutionary selection- the adverse effects of opiates in this case- resulted in unprecedented survival privileges (38). With their capability of decreasing testosterone levels (39), narcotics may have regulated and modified testosterone levels to flourish and maintain humans’ survival by addressing the other aspects of survival other than reproduction.
However, one might question the assumption indicating that testosterone decline in early male humans was a direct consequence of opiate consumption. In this regard, we suggest a two-level model explaining the role of opiates in expediting human civilization. Disregarding the civilization-promoting mechanism of opiates, this model assumes that some male humans happened to evolve during the unknown process(es) such as climate change at the end of the last ice age (40) or living under harsh environmental conditions (41). This was also accompanied by a declining testosterone level, making them be domesticated, sociable (42), and environment-conscious (43). This group of male humans could form families, have better access to females within familial colonies, and promote their genetic inheritance. One the other hand, those males who had not benefitted from that evolutionary modification and continued to have high testosterone remained marginalized with much less access to females and the higher risk of extinction. Considering different alimentary, physical, and mental effects of opium poppy, there is a good reason to believe that the marginalized males might have used opiates to benefit from its pleasant properties. Incidentally, opiates resulted in lower testosterone and helped the marginalized group of male humans to neutralize within domesticated human colonies. To sum up, opiate use augmented the civilization of humans by adding different numbers of domesticated males to human colonies. According to Hamilton’s rule (27), humans enjoyed the effect of opiates on testosterone reduction and subsequent neutralization in colonies. Moreover, opiate using behavior should have resulted in epigenetic modifications reinforcing opiate use.
2. Arguments
2.1. Dilemma of Testosterone Level
In animal studies, opioids generally suppress testosterone (44). Studies on testosterone levels in human opiate users, however, are neither rich nor conclusive. Interestingly, some studies have reported a decrease in testosterone level in about half of the cases (45), while others noticed normal or even maximum high testosterone levels (46). Human studies show that factors other than opioids, including age (47), number of comorbidities (47), cognitive decline (48), and body mass index (49), play a role in opioid-related testosterone reduction in both men (49) and women (50). Nonetheless, the influence of opiates on the endocrine system (51) and particularly on lowering testosterone (52) remains an area of debate. A possible explanation for inconsistencies between animal and human studies is that unlike animal studies that begin with healthy animals and the researcher creates a pathology in the animal (53), human studies have generally been on patients or long-term substance-using individuals; thus, the influence of coexisting pathologies on testosterone in humans might not be the same as that in lab animals (54). Furthermore, in animal studies, the researcher can measure the base level of the biological agent (i.e., testosterone) prior to interventions, while, at least for testosterone level, this has not been the case in many human studies. Moreover, an underlying complication is the significant variability in total and free testosterone serum levels due to intraindividual variation (55). The serum testosterone level even appears to be dependent on social status and fluctuates accordingly (56).
Higher testosterone levels influence social behaviors and reduce fear and anxiety (57) as well as violence (58). This mechanism has a surviving effect during wartime, where increased testosterone has been evidenced following troops' deployment in combat zones (59). Interestingly, however, as the Vietnam war extended, a heroin epidemic ensued among the servicemen (60). Moreover, heavy exercises and athletic activities are typical reasons explaining why human beings take exogenous testosterone and other anabolic steroids (61). Evidently, opioid use is more prevalent among athletes and bodybuilders taking exogenous testosterone (62). One may, hence, conclude that we are preprogrammed to reduce high testosterone levels by using opioids, and that the propensity for using opioids in response to high testosterone levels is rooted in the same evolutionary mechanism, making early humans domesticate and be civilized. In other words, instead of a side effect, the effect of the opioid on suppressing testosterone may be the nature's solution to the higher than expected level of testosterone. Referring to the fact that civilized humans have lower testosterone levels, one may further argue that opiates have played a critical role in this respect. Humans might have started using opiates for their pain-relieving effect. However, in the interim, opiates promoted civilization in the human species by suppressing testosterone.
Given that the evidence on serum testosterone level in subjects who use opioids for non-medical purposes is inconclusive, according to the fifth edition of the diagnostic and statistical manual of mental disorders (63), at least some individuals who may receive a label of an opioid use disorder, may have started using opioids under the influence of the evolutionary propensity for modifying high testosterone level by using opioids simply in response to their high testosterone level. Interestingly, the contradictory evidence on the effect of opioids on testosterone level (46) may also support this hypothesis since the measured testosterone level in individuals who use opioids has been below normal, normal, or even above normal. This model might even explain why some individuals benefit from methadone maintenance more than others regarding their baseline testosterone level (45). According to the above hypothesis, the normal and above normal testosterone levels in the presence of opioid use would still be predictable. In those cases, either the opioid dose has not been as high enough to suppress testosterone, or the baseline testosterone level has been too high to be subdued by opioids.
3. Conclusions
3.1. Future Considerations
The literature on opioids’ effect on human testosterone level is inconclusive; hence, further studies are recommended to address this issue. Our observation (63) shows that testosterone levels in clients undergoing opioid substitution therapy might be subnormal, normal, or above-normal. In this regard, a focus on opioid dosage in association with testosterone level seems to be of greater significance. Stimulants, such as tobacco (nicotine), seem to play a similar role as opiates in reducing testosterone (64, 65), albeit with much less efficacy. An investigation of similarities between nicotine and opioids in modulating testosterone levels might open new frontiers in understanding underlying factors for the compulsive use of those substances in at least a group of individuals who become dependent on those substances. Differentiation has been made between proactive aggression and reactive violence and the causal effects of modernization and population in the development of aggressive behaviors (66). Studies on testosterone changes during wartime and its association with opioid use would also contribute to providing better biological descriptions and explanations on the roots of the tendency for war in human beings and peace-boosting methods.
We hypothesize that opium has played a role in the civilization of early humans by augmenting the suppression of male human testosterone levels. We further argue that the propensity for using opioids in some contemporary humans might result from the genetic and epigenetic footprints of opiates' effects on early humans.
