Most adults regularly use at least one psychoactive drug. Globally popular options include caffeine (found in coffee, tea, soft drinks, and chocolate), alcohol, nicotine, arecoline and other psychoactive compounds in areca nuts (i.e., betel nuts, used by 10-20% of the global population), THC and other cannabinoids, opioids, amphetamine and its chemical analogs found in khat and other plants, and cocaine (Gupta & Warnakulasuriya, 2002; Peacock et al., 2018; Verster & Koenig, 2018). Few realize, however, the extraordinary time depth in which people have been interacting with these plants. The most influential scientific account of human psychoactive substance use focuses on the mesolimbic dopamine system (MDS), a collection of dopamine neurons in the midbrain of humans and many other animals that plays a central role in Pavlovian conditioning and similar types of reinforcement learning. According to this view, the MDS evolved to reinforce behaviors that increased access to so-called natural rewards, such as food, sex, and other necessities of survival and reproduction (Glimcher, 2011; Wise, 1996). Surprisingly, many popular psychoactive drugs also stimulate the MDS. This fact provides for a compelling theory of drug use: Drugs happen to activate behaviorreinforcement circuitry in the brain, thereby reinforcing drug consumption (cf. Nutt, Lingford-Hughes, Erritzoe, & Stokes, 2015; Everitt & Robbins, 2016; Koob & Volkow, 2010; Wise, 1996). But it also raises an important question: Why would drugs, which are often harmful to the user, activate brain circuitry that evolved to reinforce biologically beneficial behaviors like obtaining food and sex?