metabolites, including alkaloids like nicotine, morphine, and cocaine, are potent neurotoxins that evolved to deter and punish herbivore consumption of the plant soma not encourage/reward it. researchers highlight that it is evolutionarily disadvantageous for plants to produce toxins that plant predators (e.g. humans) are attracted to, and that it runs contrary to evolutionary logic that plant predators (e.g. humans) would evolve neurobiological systems unprotected from plant toxin consumption. proponents of the hijack hypothesis outline a path to addiction that involves drugs co-opting neural reward systems intended for food. however, research on murine models has shown that when the concentration is sufficiently high, sugar operates as a more robust reward than even cocaine. in laboratory conditions, where rats are presented with both a sugar and cocaine sipper, they choose sugar. researchers use these findings to suggest that sugar reward might generate a stronger dopamine stimulation than cocaine and also may make use of neural mechanisms beyond dopamine stimulation. alternative mechanisms explain continued tobacco use: the majority of first time users of cigarettes report adverse reactions, including nausea, dizziness, sickness, and headache. a study by difranza et al. (2004) found that 69% of subjects rated inhaling their first cigarette as bad, and nearly three-quarters (72%) reported that their first cigarette made them not want to smoke again. given the above, opponents of the reward model of drug use suggest it is likely that a mechanism other than a false perception of an increased fitness benefit via hijacking of the brain's mesolimbic dopamine system, is leading to continued tobacco use. pharmacophagy hypothesis throughout the course of human evolution, the importance of psychoactive plant substances for health has been enormous. since our earliest ancestors chewed on certain herbs to relieve pain, or wrapped leaves around wounds to improve healing, natural products have often been the only ways of treating disease and injury. plants provide fitness benefits. upwards of 25% of all pharmaceutical drugs are from plant-derived sources. the us national cancer institute has identified over 3,000 plants that are effective against cancer cells. almost all major recreational drugs are secondary plant compounds or a close chemical analog. it is well established that in both present and past contexts plants have been used for medicinal purposes. a core premise of evolutionary theory is that a trait cannot evolve unless it contributes to an individual's reproductive fitness. proponents of the pharmacophagy hypothesis/medicinal model of drug use suggest that pharmacophagy, the consumption of pharmacological substances for medicinal purposes, evolved in the backdrop of human-plant coevolution as a means of self-medication. theorists propose that the reason humans learned to ignore the cues of plant toxicity (e.g. bitter taste) and consumed potentially lethal substances with little to no energetic content because ingesting the bioactive compounds of plants in small amounts was therapeutic. though the long-term health costs of drug use are undeniable, proponents of the medicinal model of drug use suggest it is possible that regulated consumption of plant neurotoxins was selected. in this regard, researchers have argued that the human brain evolved to control and regulate the intake of psychoactive plant toxins in order to promote reproductive fitness. broadly, theorists suggest that plant toxins were deliberately ingested by human ancestors to combat macroparasites (e.g. parasitic worms) and/or to ward off disease-carrying vectors (e.g. mosquitos). nicotine as an anthelminthic for example, researchers have recently sought to understand why humans began using tobacco in spite of the consequences and adverse reactions commonly associated with its use. hagen and colleagues propose that, as in other species, humans began using tobacco and other plant toxins as a way of controlling infection by parasitic diseases, including helminths. tobacco, as well as arecoline and cannabis, two other plant neurotoxins that are widely used as recreational drugs in humans, have been found to be toxic to parasitic worms that affect humans and other mammals, as well as plants. modern anthelminthics function as well by targeting nicotinic acetylcholine receptors (nachrs) on somatic muscle cells of parasites, producing paralysis and expelling the parasite, the same receptors which are targeted by nicotine (roulette et al., 2014). moreover, it has also been found that nicotine is equally or more effective than commercial anthelmintics at killing leeches, including those that infect humans. similarly, roulette et al. (2014) found in a study comparing male smoking prevalence and parasite load among aka hunter-gatherers that treatment with commercial anthelmintics was associated with a decrease in cotinine concentrations (a measure of current tobacco use), thereby supporting their theory that humans regulate the amount of tobacco used in response to current helminth infection. the study also found that men with higher initial tobacco use also had lower worm burdens one year later, suggesting that nicotine not only eliminates parasites, but also protects from reinfection. sexual selection hypothesis some evolutionary psychological theories concerning drug use suggest individuals consume drugs to increase reproductive opportunities. drug use can increase reproductive fitness because drug use can (1) advertise biological quality, sexual maturity, or availability, (2) decrease inhibitions in mating contexts, and/or (3) enhance associative learning behaviors that in turn increase mating opportunities. see richardson et al., 2017 for a review. advertising biological quality researchers suggest that because variation in drug use susceptibility is in part due to genetic factors, drug consumption could potentially be a costly and honest signal of biological quality. the hypothesis being that humans engage in substance use despite health costs in part to evidence that they can afford to do so. to test the effects substance use had on indicators of mating success researchers tested the effect an individual's fluctuating asymmetry had on the propensity/likelihood to use drugs and found no significant results. advertising sexual maturity hagen et al. (2013) suggest that individuals use drug substances to signal maturity. they point out that sexually selected cues of quality often emerge in adolescence (e.g. the peacock's tail) and reliably signal developmental maturity. the teratogenic effects of addictive substances are well documented, as is the fact that psychoactive substances are most harmful to individuals who are developmentally immature. although this hypothesis remains untested, evidence in support comes from age at onset of drug use. unequivocally, tobacco consumption does not occur prior to age 11 and in almost all cases, this aligns with age at onset of drug use, as cigarette addicts report having first smoked in adolescence. hagen et al. suggest the reason drug use most often occurs in adolescent populations is due to the developmental maturity of the adolescent nervous system as well as the increased competition to compete for mates. consistent with these notions, researchers have found that adolescents with alcohol use disorders were more sexually active, had more sexual partners, and initiated sexual activity at slightly albeit younger ages. decreasing inhibitions another possible explanation to the prevalence of substance use is that it contributes to mating success by altering brain functions that lower inhibitions. generally, people seem to believe substance use will enhance their social behaviors in ways conducive to mating success. research has shown that many drug types inhibit prefrontal cortex neural activity, the area of the brain responsible conducting long term gains and short term costs. alcohol myopia theory suggest alcohol lowers inhibitions and amplifies the pre-drinking intention to have sex. research has also shown that alcohol stimulates dopamine activity in the mesolimbic-dopamine system, which amplifies the salience of natural rewards (e.g. finding food and mates) in the present environment and boost associative learning. evolutionary approaches to age and sex differences in drug use drug use is not evenly distributed in the population. research has shown that the prevalence of substance use problems varies in fairly reliable ways according to age, sex, and sociodemographic characteristics. overall, and across drug categories—including alcohol, coffee, cannabis, and nicotine—men make up the primary drug demographic. research has also shown that the prevalence of substance use disorders is highest among young adults (ages 18–29), and among individuals of low socioeconomic status. application of evolutionary theory to patterns of drug use suggest patterns can be explained in terms of the fundamental trade-offs that occur during different developmental periods as well as gender differences arising from reproductive asymmetry. according to life history theory, individuals have finite energetic resources and thus face energetic allocation decisions concerning investment in maintenance, growth, and reproduction. how resources are allocated to these different tasks in order to most effectively maximize reproductive fitness will depend on the age and sex of the individual and the environmental context the individual exists in. sex differences life history predicts that men, especially if they are young, are most likely to engage in drug use because they are most likely to engage in risky behavior and discount the future. young men have the most to gain from risk-taking behavior because competition for mates, status, and resources is greatest during late adolescence and young adulthood. as men age, they are more likely to develop long-term pair-bonds, accrue status, and have children, thus as men age life-history theory predicts a decrease in risk-taking behavior and a reallocation of energy to parenting rather than mating. the average age at drug initiation occurs in adolescence (ages 15–25) and supports this shift. in contrast, life-history theory predicts that women are less prone to engage in risk-taking behavior because they experience less variance in reproductive success and have more to lose from risk-taking and more to gain from focusing effort on parenting. the fetal protection hypothesis: almost all major recreational drugs are secondary plant compounds or a close chemical analog and are thus teratogenic, substances known to cause congenital abnormalities and other reproductive harms (e.g. nicotine, carbon monoxide, hydrogen cyanide). give sex-specific vulnerabilities and fitness costs, the fetal protection hypothesis proposes that selection for increased drug avoidance could have evolved in women to protect them from harming their developing fetuses and nursing infants. ancestral women and conditions: in the environment of evolutionary adaptation (eea), selection pressures shaping avoidance of or defenses against teratogenic substances would have been high. evidence from evolutionary anthropology suggest ancestral women, similar to women in extant hunter gatherer populations, experienced high fertility and high infant mortality. importantly, high fertility is characterized by short inter-birth intervals, early age at first birth, and periods of breastfeeding spanning upwards of two years. given such high reproductive costs, it is likely the fitness cost of ingesting neurotoxins is higher for women than men. one such hunter-gatherer population, the aka, have incredibly high smoking prevalence rates among men (95%), but very low rates among women (5%). drugs and negative fertility endpoints: studies have shown that fetal exposure to nicotine is associated with a range of negative outcomes before and during parturition as well as for the baby early and later in life. it has also been shown that cigarette smoking has a significant negative effect on the clinical outcome of assisted reproduction treatments, with smokers requiring higher mean gonadotropin doses for ovarian stimulation and requiring nearly twice the number of in vitro fertilization cycles to conceive. female specific defenses: compared to men, women metabolize toxins at faster rates and detect the presence of toxins at lower concentrations. ovarian hormones have been implicated in the activity of xenobiotic metabolism. research on pregnant women has documented the differential effects of estrogen and progesterone on the expression of cyps in response to cigarette smoke. using hepatic cells, choi et al., (2012) found that progesterone and estradiol altered drug metabolism but only when hormone concentrations reach that which is normal for pregnancy. changes in xenobiotic metabolism in women using birth control also suggest hormonally mediated influences. specifically, changes in hepatic drug elimination for cyp1a2, cyp2c19 and cyp2a6 are similar in pregnant women and non-pregnant women using hormonal contraception. furthermore, in women across the menstrual cycle, smoking topography variables (e.g. total number of cigarettes smoked, mean puff volume, etc.) seem to be mediated by estradiol and progesterone. in various studies, regular smokers have been shown to produce approximately one-third less estrogens (including estradiol) during the postovulatory menstrual phase than non-smoking counterparts. research suggests the reason for this relationship is due to a functional tradeoff, with the enzymes that metabolize estradiol instead metabolizing/detoxifying tobacco toxins.