HYPOTHESIS AND THEORY ARTICLE published: 05 November 2013 PSYCHIATRY doi: 10.3389/fpsyt.2013.00142 Explaining human recreational use of ‘pesticides’: the neurotoxin regulation model of substance use vs. the hijack model and implications for age and sex differences in drug consumption Edward H. Hagen1*, Casey J. Roulette 1 and Roger J. Sullivan2 1 Department of Anthropology, Washington State University, Vancouver, WA, USA 2 Department of Anthropology, California State University, Sacramento, CA, USA Edited by: Most globally popular drugs are plant neurotoxins or their close chemical analogs. These Hanna Pickard, University of Oxford, compounds evolved to deter, not reward or reinforce, consumption. Moreover, they reliably UK activate virtually all toxin defense mechanisms, and are thus correctly identified by human Reviewed by: Serge H. Ahmed, Centre national de neurophysiology as toxins. Acute drug toxicity must therefore play a more central role in la recherche scientifique, France drug use theory. We accordingly challenge the popular idea that the rewarding and rein- Bennett Foddy, University of Oxford, forcing properties of drugs “hijack” the brain, and propose instead that the brain evolved to UK carefully regulate neurotoxin consumption to minimize fitness costs and maximize fitness *Correspondence: benefits. This perspective provides a compelling explanation for the dramatic changes in Edward H. Hagen, Department of Anthropology, Washington State substance use that occur during the transition from childhood to adulthood, and for perva- University, 14204 NE Salmon Creek sive sex differences in substance use: because nicotine and many other plant neurotoxins Avenue, Vancouver, WA 98686-9600, are teratogenic, children, and to a lesser extent women of childbearing age, evolved to USA avoid ingesting them. However, during the course of human evolution many adolescents e-mail: [email protected] and adults reaped net benefits from regulated intake of plant neurotoxins. Keywords: pharmacophagy, zoopharmacognosy, drug reward, evolution, self-medication, evolutionary medicine The mesolimbic dopamine system (MDS)1 plays a key, though [e.g., Ref. (7–15)]. Kelley and Berridge [(9), p. 3306], for instance, still not fully understood, role in the ability of laboratory ani- open their review with: mals to learn an association between a stimulus, such as a tone, Addictive drugs act on brain reward systems, although the and a natural reward, such as sugar water, and to approach and brain evolved to respond not to drugs but to natural rewards, consume the reward (1–6). Drugs of abuse have neurobiological such as food and sex. Appropriate responses to natural and behavioral effects that closely resemble the effects of sugar rewards were evolutionarily important for survival, repro- and other natural rewards, activating the MDS and producing duction, and fitness. In a quirk of evolutionary fate, humans approach and consummatory behavior, positive feelings, and the discovered how to stimulate this system artificially with drugs. learning of cues that predict drug availability. Drugs are rewards (7). Moreover, drugs and sugar are chemically similar: both are In another review, Hyman [(11), p. 1414] leads into a section titled small organic molecules that act as ligands for various receptors. “A Hijacking of Neural Systems Related to the Pursuit of Rewards” In fact, fermentation converts 1 glucose molecule into 2 ethanol with: molecules (and 2 CO molecules), and ethanol contains more 2 [A]ddiction represents a pathological usurpation of the calories per gram than glucose (7 vs. 4), underscoring the compa- neural mechanisms of learning and memory that under nor- rability of a natural reward and a drug. On what basis, then, do mal circumstances serve to shape survival behaviors related neurobiologists classify drug reward as abnormal and food reward to the pursuit of rewards and the cues that predict them. as normal? On the evolutionary novelty of drug dependence, Wise [(8), p. 27] 1. THE HIJACK HYPOTHESIS is perhaps most explicit: Numerous, highly cited articles that review the neurobiology Addiction is quite a recent phenomenon, largely depen- of drug use employ similar metaphors to distinguish nat- dent upon the controlled use of fire (smoking), hypodermic ural rewards from drugs: natural rewards “activate” the MDS, syringes (intravenous injection), and the cork and bottle whereas drugs“hijack,”“usurp,”“co-opt,”or artificially stimulate it (storage and transportation of alcohol). Thus, while brain dopamine is activated by most drugs of abuse, the drugs have 1The MDS comprises dopamine (DA) neurons located in the midbrain structures undergone mostly human selection for their ability to activate of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) that the system; the system has not undergone natural selection project to the nucleus accumbens (NAc) and dorsal striatum. because of its sensitivity to the drugs. www.frontiersin.org November 2013 | Volume 4 | Article 142 | 1 Hagen et al. Explaining human recreational use of “pesticides” We refer to these arguments as the “hijack hypothesis.” We rec- 2. MOST DRUGS ARE PLANT DEFENSIVE CHEMICALS OR ognize, on the one hand, that this is a metaphor invoked by CLOSE CHEMICAL ANALOGS drug researchers to help explain the effects of drugs of abuse Terrestrial plants and animals appeared s400 million years ago. on the brain. On the other hand, its frequent appearance in Animals evolved to exploit plant tissues and energy stores, and prominent review articles suggests that drug abuse researchers in response, plants evolved numerous defenses, including toxins. consider it to provide a fundamental distinction between addictive These toxins appear in high concentrations in some organs, like substances and food. This distinction is based on the follow- leaves, that are critical for plant growth, survival, and reproduc- ing Darwinian propositions: the MDS evolved to enhance access tion, and in low concentration in other organs, like ripe fruits, that to some substances, like sugar, that increased fitness2; these are evolved to be consumed by herbivores to aid seed dispersal, which termed “natural rewards.” It did not evolve to respond to known is beneficial for the plant. drugs of abuse because these did not increase fitness and because Plant drugs, such as caffeine, nicotine, cocaine, and THC, repeated consumption of such substances is an evolutionary belong to a subcategory of toxins that evolved to interfere with novelty3. neuronal signaling in herbivores. Depending on the toxin, this Unfortunately, most drug researchers do not seem to regard the includes interference with: (1) neurotransmitter synthesis, storage, hijack hypothesis as a hypothesis. Instead, it is treated as an axiom release, binding, and re-uptake, (2) receptor activation and func- or truism that requires little supporting evidence. The most impor- tion, and (3) key enzymes involved in signal transduction (24). tant point of our commentary is that the evolutionary premises of Plant drugs therefore did evolve to “hijack” herbivore nervous sys- the hijack hypothesis are empirically testable. tems, but for an effect that is precisely the opposite of the hijack Previous work has criticized the hijack hypothesis on a number hypothesis: to deter, not reward, or reinforce, plant consumption. of grounds (see, for instance, articles in this special issue). In par- (We prefer describing these effects as “interference” rather than ticular, although laboratory studies demonstrate that animals will “hijacking.”) self-administrate most drugs of abuse, these studies rarely provide Plant toxins have had a profound influence on the evolution of the animals with alternative rewarding choices. In studies that do herbivore neurophysiology, resulting in: (1) numerous chemosen- provide a rewarding alternative, such as sweetened water or social sors including bitter taste receptors,(2) detoxification mechanisms interactions (as in the famous Rat Park experiment), most animals including cytochrome P450 and other enzymes, (3) cellular mem- choose the alternative, not the drug, undermining the claim that brane carrier proteins for toxin transport, including ATP-binding drugs hijack decision-making machinery (19). cassette proteins, and (4) aversive learning mechanisms that per- Here we briefly summarize our previous critique of the mit selective feeding on less toxic tissues (25, 26). Many herbivore hijack hypothesis’ evolutionary premises (20–22). It is impor- defensive proteins are expressed in the blood-brain barrier and tant to emphasize that we only critique these premises, not the the brain itself, including in humans (27–30), indicating the fit- evidence on the neurobiological mechanisms involved in drug ness advantages of protecting the CNS specifically from plant use nor the various interpretations of dopamine function. We neurotoxins and other xenobiotics. then sketch an evolutionary alternative to the hijack hypothesis: From an herbivore’s perspective, then, the value of a plant the neurotoxin regulation hypothesis. We conclude by consider- substance usually comprises the benefits of useable macronutri- ing age and sex differences in substance use in light of both ents (carbohydrates, fats, and proteins) minus the costs of toxin hypotheses. exposure. A caveat: neurobiological theory of drug use usually contrasts initial seeking and use with longer-term phenomena such as 2.1. BENEFITS OF TOXIN CONSUMPTION IN NON-HUMAN ANIMALS drug tolerance and addiction.