Roger J. Sullivan

Revealing the paradox of drug reward in human evolution

Neurobiological models of drug abuse propose that drug use is initiated and maintained by rewarding feedback mechanisms. However, the most commonly used drugs are plant neurotoxins that evolved to punish, not reward, consumption by animal herbivores. Reward models therefore implicitly assume an evolutionary mismatch between recent drug-profligate environments and a relatively drug-free past in which a reward centre, incidentally vulnerable to neurotoxins, could evolve. By contrast, emerging insights from plant evolutionary ecology and the genetics of hepatic enzymes, particularly cytochrome P450, indicate that animal and hominid taxa have been exposed to plant toxins throughout their evolution. Specifically, evidence of conserved function, stabilizing selection, and population-specific selection of human cytochrome P450 genes indicate recent evolutionary exposure to plant toxins, including those that affect animal nervous systems. Thus, the human propensity to seek out and consume plant neurotoxins is a paradox with far-reaching implications for current drug-reward theory. We sketch some potential resolutions of the paradox, including the possibility that humans may have evolved to counter-exploit plant neurotoxins. Resolving the paradox of drug reward will require a synthesis of ecological and neurobiological perspectives of drug seeking and use.

The crisis of psychiatry — insights and prospects from evolutionary theory

Darwin’s emphasis on natural selection has had a transformative influence on how biological and medical sciences are conceptualized and conducted. However, the relevance of his ideas for the understanding of psychiatric conditions is still under-appreciated. Modern understanding of disease has required appreciation of the dialectical give and take between environmental influences, life history theory imperatives, human behavioral ecology, and characteristics of adaptive processes at all levels of the individual. This has enabled a better comprehension of metabolic disturbances, cancers, auto-immune disease, inherited anemias, and vulnerability to infectious disease 1. Here we propose that a contemporary and scientifically satisfying understanding of psychiatric conditions requires adopting a similar logic of inquiry, by taking into consideration the influence of environmental contingencies and natural selection in sculpting not just brain based mechanisms and processes germane to clinical neurosciences, but also diverse characteristics of behavior. One approach to understand psychiatric disorders in an evolutionary perspective builds upon Nobel laureate Nikolaas Tinbergen’s ideas, suggesting that, for a full understanding of any given phenotypic trait, one needs to detect the development and nature of its mechanisms, construed as the “proximate causes”, and, in addition, its evolutionary (or phylogenetic) history and adaptive value 2. Studying the proximate mechanisms is standard in psychiatry and the clinical neurosciences, but the questions pertaining to the phylogeny of traits have largely been ignored. Admittedly, placing dysfunctional cognitive, emotional and behavioral processes in the context of possible adaptation is not straightforward at first sight. The clinical directive requires that “disorder” represent the appropriate focus. However, a “disorder” – by definition – is counter-intuitive in the context of adaptation. By adaptation we mean a genetically-mediated structural or behavioral trait, which when possessed, increased survival and reproductive success in the environment in which the trait evolved. Were psychiatry’s focus be placed on “traits” (i.e., cognitive processes, emotions, and behaviors), problems which are clinically relevant could more satisfactorily be understood as distorted expression of mechanisms that in earlier environments provided answers to problems of adaptive significance, but which currently interfere in light of prevailing environmental contingencies 3. Important to the understanding of a particular phenotype is the evolutionary concept of variation. Without variation, no evolution by natural selection could take place. Mainstream psychiatry has largely ignored the fact that variation is the rule, not the exception, and this creates conceptual tensions. Psychiatry conceptualizes “disorder” as a statistical deviation from a normative statistical mean, yet handles it as a category. In other words, both “normalcy” as well as “disorder” with regard to psychological or behavioral functioning are burdened with the connotation of low variation. Phenotypic variation is the result of a complex interplay of genotype and environment, including epigenetic mechanisms that are decisively shaped by experience over the individual lifespan. These issues translate to providing a clinician with a rationale for explaining why, how, and when adaptive behavior is compromised and constrained; that is, when social, cultural, or ecological conditions and circumstances pose hindrances or risks which interfere with achievement of best solutions to socio-biological problems, and which may require a modification of a strategy of coping, selection of an alternative strategy, and/or the setting of more realistic biological goals. This integrative view of psychopathology, we believe, can have profound effects on how psychiatry conceptualizes disorders, which shall be illustrated briefly in three examples.

ECOLOGY AND NEUROBIOLOGY OF TOXIN AVOIDANCE AND THE PARADOX OF DRUG REWARD

Current neurobiological theory of drug use is based on the observation that all addictive drugs induce changes in activity of dopaminergic circuitry, interfering with reward processing, and thus enhancing drug seeking and consumption behaviors. Current theory of drug origins, in contrast, views almost all major drugs of abuse, including nicotine, cocaine and opiates, as plant neurotoxins that evolved to punish and deter herbivores. According to this latter view, plants should not have evolved compounds that reward or reinforce plant consumption. Mammals, in turn, should not have evolved reinforcement mechanisms easily triggered by toxic substances. Situated in an ecological context, therefore, drug reward is a paradox. In an attempt to resolve the paradox, we review the neurobiology of aversive learning and toxin avoidance and their relationships to appetitive learning. We seek to answer the question: why does aversive learning not prevent the repeated use of plant drugs? We conclude by proposing alternative models of drug seeking and use. Specifically, we suggest that humans, like other animals, might have evolved to counter-exploit plant neurotoxins.

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

Most globally popular drugs are plant neurotoxins or their close chemical analogs. These compounds evolved to deter, not reward or reinforce, consumption. Moreover, they reliably activate virtually all toxin defense mechanisms, and are thus correctly identified by human neurophysiology as toxins. Acute drug toxicity must therefore play a more central role in drug use theory. We accordingly challenge the popular idea that the rewarding and reinforcing properties of drugs “hijack” the brain, and propose instead that the brain evolved to carefully regulate neurotoxin consumption to minimize fitness costs and maximize fitness benefits. This perspective provides a compelling explanation for the dramatic changes in substance use that occur during the transition from childhood to adulthood, and for pervasive sex differences in substance use: because nicotine and many other plant neurotoxins are teratogenic, children, and to a lesser extent women of childbearing age, evolved to avoid ingesting them. However, during the course of human evolution many adolescents and adults reaped net benefits from regulated intake of plant neurotoxins.

Blood donations as costly signals of donor quality

This is the first empirical investigation of blood donations in evolutionary perspective. We examine blood donor and non-donor attitudes about health and injury risks, donor characteris- tics, and the social value of donor participation. We propose that blood donations may communi- cate qualities about donors to third parties. Observers may benefit from information about the do- nors health, value as a reciprocal partner, and/or ability to endure what is perceived as an anxi- ety-provoking and risky experience. Donors may benefit from an enhanced reputation, which can lead to greater access to cooperative networks and high-quality partners. We found that partici- pants recognized the need for blood and perceived blood donors as generous and healthy. Study results indicated that anxiety and the perceived risk of a negative health consequence dramatically affected the willingness of donors and non-donors to donate blood in the future. These findings support our hypothesis that the act of blood donation may signal adaptive information about do- nor quality to third parties.

The low prevalence of female smoking in the developing world: gender inequality or maternal adaptations for fetal protection?

Background: Female smoking prevalence is dramatically lower in developing countries (3.1%) than developed countries (17.2%), whereas male smoking is similar (32% vs 30.1%). Low female smoking has been linked to high gender inequality. Alternatively, to protect their offspring from teratogenic substances, pregnant and lactating women appear to have evolved aversions to toxic plant substances like nicotine, which are reinforced by cultural proscriptions. Higher total fertility rates (TFRs) in developing countries could therefore explain their lower prevalence of female smoking. Objective: To compare the associations of TFR and gender inequality with national prevalence rates of female and male smoking. Methods: Data from a previous study of smoking prevalence vs gender inequality in 74 countries were reanalysed with a regression model that also included TFR. We replicated this analysis with three additional measures of gender equality and 2012 smoking data from 173 countries. Results: A 1 SD increase in TFR predicted a decrease in female smoking prevalence by factors of 0.58–0.77, adjusting for covariates. TFR had a smaller and unexpected negative association with male smoking prevalence. Increased gender equality was associated with increased female smoking prevalence, and, unexpectedly, with decreased male smoking prevalence. TFR was also associated with an increase in smoking prevalence among postmenopausal women. Conclusions: High TFR and gender inequality both predict reduced prevalence of female smoking across nations. In countries with high TFR, adaptations and cultural norms that protect fetuses from plant toxins might suppress smoking among frequently pregnant and lactating women.

Competitive Status Signaling in Peer-to-Peer File-Sharing Networks

Internet peer-to-peer file sharing is a contemporary example of asymmetrical sharing in which “altruists” (file uploaders) share unconditionally with non-reciprocating “free riders” (file downloaders). Those who upload digital media files over the Internet risk prosecution for copyright infringement, and are more vulnerable to computer hackers and viruses. In an analysis of file-sharing behavior among university undergraduates (N=331), we found that significantly more males than females engaged in risky file uploading. Contrary to expectations, uploaders were not concerned about their reputation online and file sharers were not interested in identifying or chatting with uploaders while online. Among uploaders, males were more likely than females to be identified as uploaders by friends, to discuss uploading and to upload in the presence of peers. We interpret these results using costly-signaling theory, and argue that uploading is a costly signal in which males engage in avoidable risk taking as a means to compete for status among peers in social contexts other than the Internet.

Schizophrenia in Palau: A Biocultural Analysis

The Republic of Palau in the western Pacific has one of the highest rates of schizophrenia diagnoses in the world today. The expression of schizophrenia in Palau and greater Micronesia is also extraordinarily gendered, with rates of affliction approximately two times higher among males. This study uses contemporary clinical diagnostic and research tools to consider and reject the hypotheses that schizophrenia in Palau has a unique diagnostic profile, that it has a unique bio‐behavioral expression, and that it is a consequence of “development” manifest in the introduction and use of psychoactive drugs. These results are used to critique an assumption that has emerged from previous cross‐cultural research—that the expression of schizophrenia is necessarily more benign in “developing” settings—and to suggest that aspects of historical and contemporary social practices may contribute to a gender imbalance in the expression of symptoms of schizophrenia in this Pacific Island nation.

The dopamine puzzle

Recently, Brischoux et al. (1) proposed that dopamine neurons in the ventral part of the ventral tegmental area (VTA) respond to aversive stimuli. Classically, VTA dopamine neurons were regarded as responding to unexpected rewards, as implicated in reinforcement learning (2). Along with other recent studies (e.g., ref. 3), a complementary role of dopamine neurons in aversive learning is emerging. Aversive dopamine signaling points to a new role of dopamine in drug abuse. Most drugs (like nicotine or cocaine) are neurotoxins, evolved by plants to deter herbivores. It appears paradoxical that they activate herbivore reward circuitry (4). So far, drug-induced increases in dopamine were regarded as a neural correlate of reward. However, the new findings (1, 3) allow an alternative interpretation, namely that the drug-induced increase in dopamine is part of an aversive reaction to toxic substances (4). To test this hypothesis, the anatomical identification of the targets of aversion-related dopamine neurons and their separation from the reward-learning circuit is crucial. Overlapping circuits would call for revisiting the reinforcement-learning hypothesis (5). Separate circuits would mark dopamine as a key player in both reward and aversive learning. However, given the anatomical proximity of the targets of aversive- and reward-related dopamine, their interaction could be a basis for economic decision-making by weighing costs vs. benefits. To better understand mechanisms underlying drug abuse, a next step is to clarify whether addictive drugs increase dopamine levels in the reward- or in the aversive-learning circuit or in both.

Reframing the science and policy of nicotine, illegal drugs and alcohol - conclusions of the ALICE RAP Project.

In 2013, illegal drug use was responsible for 1.8% of years of life lost in the European Union, alcohol was responsible for 8.2% and tobacco for 18.2%, imposing economic burdens in excess of 2.5% of GDP. No single European country has optimal governance structures for reducing the harm done by nicotine, illegal drugs and alcohol, and existing ones are poorly designed, fragmented, and sometimes cause harm. Reporting the main science and policy conclusions of a transdisciplinary five-year analysis of the place of addictions in Europe, researchers from 67 scientific institutions addressed these problems by reframing an understanding of addictions. A new paradigm needs to account for evolutionary evidence which suggests that humans are biologically predisposed to seek out drugs, and that, today, individuals face availability of high drug doses, consequently increasing the risk of harm. New definitions need to acknowledge that the defining element of addictive drugs is ‘heavy use over time’, a concept that could replace the diagnostic artefact captured by the clinical term ‘substance use disorder’, thus opening the door for new substances to be considered such as sugar. Tools of quantitative risk assessment that recognize drugs as toxins could be further deployed to assess regulatory approaches to reducing harm. Re-designed governance of drugs requires embedding policy within a comprehensive societal well-being frame that encompasses a range of domains of well-being, including quality of life, material living conditions and sustainability over time; such a frame adds arguments to the inappropriateness of policies that criminalize individuals for using drugs and that continue to categorize certain drugs as illegal. A health footprint, modelled on the carbon footprint, and using quantitative measures such as years of life lost due to death or disability, could serve as the accountability tool that apportions responsibility for who and what causes drug-related harm.