Evolutionary Medicine: A Focus on Migraine and Psychiatry

Lawrence Robbins, MD

 Evolutionary Medicine is a growing, vital, fascinating and relevant area. I use it daily in my practice, to explain to patients (such as the evolutionary reason for anxiety, why we have so much neck and back pain, why we suffer pain and mortality with childbirth etc…) it should be taught in our medical, nursing, and physician assistant (PA) schools. We could avoid problems by studying evolution.  How best to use antibiotics, and how avoiding blocking certain compounds that are crucial for 400 million years such as CGRP, which certain migraine drugs block, are two examples of how understanding evolution could benefit patients. We ignore evolution “at our peril”.

A Bit O’ History

  • Darwin thought along evolutionary lines: ERASMUS DARWIN, that is… (1790) Erasmus was the grandfather of Charles. Lamarcke (about 1805) built on his ideas. Lamarcke had the right idea (but thought an acquired trait during one’s life could be directly inherited… he believed in “spontaneous generation”)
  • Later in 1858, Charles wrote “On the Origin of Species”. He was hurried along because of Alfred Wallace; they admired each other. Similar to Rosalind Franklin of DNA discovery, Wallace has been unfairly forgotten.

Early objections to evolution (my main thesis as an undergrad) were mainly along religious grounds, and also that early proof was lacking. Although The religious arguments persisted, within 15 years evolution was scientifically accepted.

Why Study Evolution?

  • Goal of medicine is to improve health and prolong life.
  • Evolutionary medicine goals include to:
    • Help develop safer treatments, such as our new CGRP meds to prevent migraine which are possibly dangerous.
    • Change modern behaviors. Historically, we had a healthier diet, and constantly exercised, for 99% of our human existence.
    • Learn to use medications in healthier ways, such as how to manage antibiotics.
    • Help clinicians explain to patients the evolutionary reason for their conditions, such as anxiety, depression.

Proximate vs. Evolutionary

  • Proximate explanation = the nuts and bolts, such as neurochemistry, physiology, etc.
  • Evolutionary = WHY something came about
  • Proximate = a mechanical explanation
  • Evolution = the engineering design
  • Ontogeny = proximate (mechanical, “nuts and bolts”) development of an organism from fertility to egg to adult
  • Phylogeny = evolution and history of a species

Natural Selection

  • Natural selection (NS) depends upon variation.
  • NS operates mainly at the level of the gene.
  • NS involves phenotypic variations driving genotype and phenotype changes over generations.
  • Within a population, variation leads to some individuals being better suited to the environment than others. This results in adaptive changes.
  • Natural selection is going on today; as little as 8,000 years ago, nobody had the genes to digest lactase; now, the genes for lactase are present in over 70% of Northern Europeans. Even by Roman times those genes were becoming more common.

Asking the Right Question

  • The right question (Nesse/Williams): Why are we so vulnerable to various diseases?
  • The wrong question: what evolutionary advantage does each disease have? (yes, they may have advantages, but often they do not).
  • Albert Einstein said, if given 60 minutes to solve a problem, he will take 55 minutes to come up with the right question.
  • Jonas Salk: “Solutions… they come through asking the right question, because the answer pre-exists”…

6 Principles of Evolutionary Medicine

  • Randolph Nesse pioneered much of this thinking: (Nesse and Williams):
    1. MISMATCH: our environment has changed, we are adapted for a radically different (ancient) environment.
    2. TRADE-OFFS: many (most) aspects of human anatomy and physiology involve trade-offs.
    3. EVOLUTION cares about reproduction and propagating one’s genes; it DOES NOT CARE about: health, happiness, longevity (except for possibly the “grandmother hypothesis: nurture and epigenetics”).
    4. PATHOGENS can replicate much faster than humans; hours versus our 18+ years. Pathogens will usually win the evolutionary arms race.
    5. DEFENSES: many symptoms are often defenses, not diseases (fever, nausea/vomiting, cough, diarrhea).
    6. NATURAL SELECTION and evolution are LIMITED; there are constraints on what selection can do; evolution tinkers, it does not invent.

Mismatch with the Environment

  • Ten to twelve thousand years ago we began to cultivate agriculture.
  • We morphed from hunter-gatherers (H-G) — more accurately called “forager-gatherer-fisher-hunters” — to agriculture-based societies.
  • Changes in our environment include:
    • agriculture
    • a move towards dense, urban populations
    • artificial light, less sunlight, & light at night
    • Houses
    • Reading
    • Pollution
    • sterile food/water
    • solo sleeping
    • bottle feeding
    • Antibiotics
    • other medicines
    • sleep changes (less sleep)
    • steady food with less food insecurity and less fasting
    • heating and cooling
    • long-term marriage
    • birth control
    • mass media and social media
    • louder sounds
    • change in diet to high starches (beginning 14,000 years ago): led to many problems
  • Approximately 50% of diseases are strongly influenced by environmental changes (mismatch with our previous environment)

Evolution and Migraine

  • Migraines increased as we moved to more northern latitudes. Low vitamin D levels and the TRPM8 gene play a role. TRPM8 is linked to decreased sensitivity to both cold and migraine.
  • Migraine due to mismatch with our modern environment, including increased light, sound, stress, immune response (possibly tied into ridding ourselves of worms/parasites), lack of exercise, urban density (and an increase in infections), poor sleep, changes in diet, pollution, electronics and social media, etc…
  • Migraine may have occasional evolutionary advantages such as an enhanced immune response could be helpful in fighting certain infections. it is speculated that the rates of mating and fecundity among migraineurs may be increased, and more research is needed. In the past most people died of infections. If one is laid up with a migraine when a virus sweeps through, the migraine may enhance survival.
  • Why migraine is much more common in women is unclear. Migraine often decreases during pregnancy, offering a small evolutionary incentive for more pregnancies.
  • Hunting/fishing were often done more by men; migraine may pose disadvantages for these activities.
  • Women did more of the foraging; migraine may not have as much of an effect on foraging, although this is unclear.
  • Why does migraine only affect humans? It may be that our ancient human brainstem has difficulty coping with a newer cortex that is vastly enlarged. Higher cortical functions may add to our continued vulnerability to migraine.
  • Migraine could be a defense mechanism against excessive stress, noise, or light.
    • Migraineurs have an enhanced sensitivity to smells; this may be protective from toxins or viruses entering the CNS. Vomiting from a migraine may remove toxins.
    • Women with migraine (probably) have a lower incidence of Type 2 diabetes.                                                                                    
    • Activating the trigeminal nuclear complex could be protective to the migraineur.
  • If a migraineur has 100 migraines in a year, and just one protects from harm, the trade-off may be worthwhile. Evolutionarily, the cost of migraine may be inexpensive.
  • Headache and pain are adaptive. Being still in bed may help with repairing damaged tissues.
  • As mentioned, mismatch with our modern environment, with radical changes over 12,000 years, is a primary driver for the increase in migraines.
    • Cultural changes (social media etc.) also may play a role.
    • The elimination (past 140 years) of worms/parasites in our GI systems has led to an increase in autoimmune illnesses. Migraine is probably (somewhat) autoimmune.

Migraine, Evolution, and our CGRP Therapies-

  • CGRP monoclonal antibodies to prevent migraine were introduced 2018. They are effective, but these have many short term adverse effects (in the 1st 3.5 years, 50,000 adverse events reported to the FDA, and 7,000 serious ones).
    • We do not yet know long term effects. CGRP has been in animals for at least 350 million years and is ubiquitous throughout our body. Blocking CGRP for years (or decades) ignores all of it’s numerous evolutionary advantages. If we paid attention to evolution, we may not have pursued the avenue of blocking CGRP.
    • We ignore evolution at our peril!

Further reading and YouTube viewing on Evolutionary Medicine:

There are excellent books, but I recommend searching YouTube: many outstanding talks on evolution and medicine

  • Books: Why We Get Sick by Nesse and Williams, Human Errors by Lents, Good Reasons for Bad Feelings by Nesse, Evolution and Medicine by Perlman
  • Robert Sapolsky is a marvelous author and speaker (many talks on YouTube: he was Scientist of the Year (U.S.) and has a newer book out, “Behave” that incorporates evolution and behavior
  • Principles of Evolutionary Medicine by Gluckman et al., Evolutionary Psychiatry by Brune, The Third Chimpanzee by Diamond, Chaos and Life by Bird, The Evolution of the Human Head by Lieberman, Evolution In Health and Disease by Stearns et al, The Lives of the Brain by Allen, Sapiens by Harari, The Riddled Chain by McKee, Evolutionary Medicine and Health by Trevathan et al.


  • An excellent lecture is “An Evolutionary Model of Depression” by Markus Rantala
  • YouTube: There are hundreds of excellent lectures and discussions.
    • Randolph Nesse has a plethora of videos and interviews; Yale Medicine and Steven Stearns has a series of excellent videos; Nathan Lentz is outstanding; Robert Sapolsky as mentioned above, and many others.

Evolutionary Psychiatry (EP)

  • Anxiety and the “Smoke Detector Principle”
    • At the watering hole on the Savannah, if the chance of getting eaten is even 1 out of a thousand, it is worthwhile to run away every time; this is “adaptive”
    • However, if we start having panic attacks for no reason, this is “maladaptive”… the margins between adaptive and maladaptive can be blurry… and it all depends on the context in which the behavior occurs.
  • The stress response is a product of millions of years of selection. The system is usually adjusted and turned off due to its costs. These adjustments include a minimized immune response during stress along with an increased metabolism.
  • Even in fish, timid fish survive predation more than bold ones…
  • Even now, evolution is occurring: red squirrels around Chicago are disappearing, as they are bolder than the grey squirrels, and don’t run away from cars. The timid grey squirrels are surviving
  • Many behaviors are observed in humans and primates, and all the way back to fish or even fruit flies! Many animal behaviors do not change from genus to genus.
    • When emotions become maladaptive, they become a “psychiatric illness”
    • Anxiety costs energy, due to catecholamine release and cortisol depletion. Energy (or the lack of) and ATP governs much of animal behaviors and evolution.
    • Chronic stress and anxiety become maladaptive, with deleterious effects.
    • Phobias can be viewed as maladaptive forms of what would be healthy adaptive thoughts in a different environment. Phobias arise out of a perceived danger from attack, trauma, or predation. What might be a reasonable response in a context 2 million years ago is unreasonable now. We are unlikely to have problems from snakes, spiders or sharks, but these phobias persist…
  • Adolescent behavior of pushing, attention seeking, impulsivity, and aggressiveness can be an advantage for mating and reproduction. Remember, evolution cares not for how happy you are, or how long you live. Evolution cares most about propagating genes.
  • Risk taking can also help in food acquisition.
    • Male risk taking (peaks in adolescence) succeeds evolutionarily. It leads to more reproduction, but also contributes to many earlier deaths.
    • At age 20 (and most other ages), for every 100 women who die, on average 350 men die, partly due to risky behaviors. This number varies between countries. These risky behaviors lead to more procreation (which is the purpose of evolution), but also leads to death. Men are also more vulnerable to certain diseases. Men are 2 to 3 times more likely to die of cancer or heart disease. An increase in procreating, but dying earlier, is a classic trade-off.
  • ADHD could possibly have adaptive survival benefits. In the forest, it could conceivably be beneficial to be unfocused and constantly looking around. However, it is more likely that ADHD is not very beneficial, but rather it is one of many illnesses that evolution simply cannot delete out of our genome. Schizophrenia is another such illness. One percent of people are schizophrenic in almost every country. Schizophrenia results in no evolutionary advantage for survival.
  • Certain personality disorder (PD) traits (aggressiveness, salesmanship, paranoia, alpha behaviors, and the “charming- seductive” behaviors) can result in increased mating and reproduction. This is part of the reason why PDs persist. The other reason that these genes persist is the plethora of different genes involved in PD pathology. Evolution has no easy way to delete these genes.
  • DEPRESSION: The different symptoms can be adaptive — if fighting an alpha male, submissive and depressed behavior may enable immediate survival. Low mood may allow an organism to recover from an infection more easily by not moving about. Depressed people may show little movements of the eye and mouth region, avoid eye contact, speak softly, and remain socially inactive. These all have advantages in certain contexts.
  • In a situation where appeasement is necessary, and inferiority or defeat is present: the non-verbal behaviors of depression may lower aggression by others. Catatonia may be an extreme example of ancient defense mechanisms.
  • Dominance, submission, and social hierarchy are inherent in most primates (and other animals, going back 400 million years). The winner and loser in a clash ideally both remain within the group. In ancestral environments, exclusion would have meant death.
  • Human life is dependent on a complex web of interactions with other humans, more than in other primate species.
  • Why do women have more depression than men? Outside of the proximate “nuts and bolts” explanations, evolutionary sex differences play a role. Women (more than men) depend upon social support. Women have had less ability (for several reasons) to leave a bad relationship/marital situation, with depression as a consequence. This may go back to ancestral times.
  • Many theories as to why we become depressed have been put forward.
    • Early work focused on infant attachment.
    • Negative life events may trigger low mood or depression, and also loss of social status. Hunter-gatherer societies experience the low mood but not nearly as much of the depression. Depression is rampant in Western societies.
    • These theories are outlined in the excellent book by Randolph Nesse, MD: Good Reasons for Bad Feelings (2019)
  • Depression is much more prevalent in Western societies
    • Depression (and anxiety) has increased from 2008 to the present; probably mismatch with the environment (social media, smartphones, pollution, etc.) and world stresses (pandemics, politics, war)
  • As mentioned, little depression is observed among various hunter-gatherer societies, and also among the Amish.

 EP — Depression, Inflammation and evolution

  • Inflammation plays a role in depression; our “modern’ diet plays some role in this…
  • Western society has more inflammation than hunter-gatherer societies
  • Our lifestyle and subsequent mismatch with the modern environment are factors
  • GI worms/parasites downregulate our neuroimmune response; since ridding ourselves of these in the past 120 years, inflammation has skyrocketed!
  • A “depression symptomatic” approach fits into evolutionary thought: the idea is that depression is a description of a number of different symptoms but not a “disease” itself. There is some evidence that simply asking about “low mood” is just as accurate for diagnosing depression as using DSM-5 criteria. A MDD diagnosis is not that helpful in guiding specific treatments.
    • The “depressive symptomatic” approach evaluates the varying symptoms, each of which can be treated. The symptoms influence each other in a feedback loop: for instance, insomnia causes fatigue, which increases low mood, which then exacerbates insomnia.
    • If we perturb one part of this system, the system will read just itself into a new homeostasis: if we decrease the insomnia, the fatigue is lessened, and then the depression may be better.
  • Each particular symptom could be adaptive in an evolutionary sense; the symptom becomes maladaptive if it is pathologic and causes undue distress, such as panic attacks. Adaptive vs. maladaptive varies depending upon the environment and context in which it occurs.
  • Sadness/emotional pain could be adaptive in that they lead to avoidance of actions that may result in more losses.
  • Crying elicits empathy and support from other group members. Exclusion, real or threatened, from a group may lead to depression. Loss of social status or hierarchy triggers depression.
  • Fatigue helps conserve energy and may be adaptive.
  • Seasonal affective disorder (SAD) may help to conserve energy in winter. In winter if a primate hunkers down, possibly due to low mood, and does not go out in the cold, energy is conserved.

EP and Mania

  • Mania may represent the pathologic extreme of dominance behaviors. Dominance and risky behaviors may lead to increased mating and reproduction (the goal of evolution).
    • Mania could also be a compensatory mechanism to view the world as less threatening.
  • Hypomania/hypersexuality = may result in increased mating.
  • Mixed states: one theory — mania is generated more from the cognitive/cortex level, and appeasement/depressive behaviors from the reptilian (older) brain.
  • In dysphoric mania, evolutionarily the mania could offset that pervasive hypervigilant fear that is so often present.

EP, cont…

  • Selection favors traits that promote fitness in our social environment such as: cooperation, reciprocal altruism, the ability to interpret actions of others, and also to detect freeloaders within the clan.
  • Altruistic behavior lowers group stress, increasing survival of all group members.
    • What may look altruistic may actually be survival of the individual (the famous Wild Kingdom Wildebeest episode)
  • An increase in cortical neurons, and acquisition of language, resulted in more complex group behaviors.
  • Human behavior also involves mating choice, kin selection, social group living, etc. For more on human behavior, check out Robert Sapolsky’s books (particularly his book “Behave”) and YouTube talks.
  • Schizophrenia and bipolar share many genes, spread throughout the genome. Autism and schizophrenia also share similar genes.
  • The multitude of genes, spread throughout, is one reason evolution cannot easily delete “bad” genes. Mutations also play a role in creating “new” psychiatric illness. When many genes are involved it renders it impossible to cure these illnesses through any type of “gene therapy”.
    • There are exceptions, where a cure is conceivable, such as Huntington’s (a specific CAG repeat)
  • For men, appeasement and submission do NOT pay off with increased mating. However, they may enhance survival. The differences in male vs. female depression may go back millions of years.
  • For men, social status = crucial towards mating and reproduction. Higher social status = more mating.
  • Lack of social support from elderly kin leads to increased risk for depression.
  • We are clannish by nature: “The oddity effect”: animals don’t associate or align with phenotypically different individuals. This goes back to fish, birds, mammals and even plankton! Clannish nature may contribute to “otherism”, and possibly racism as well.
  • This may be the origination of human bullying (“appearance-based bullying”), and helps to explain xenophobia.
  • Within a group, those that look the most like the group tend to be the worst bulliers.

 Vasovagal syncope is probably adaptive. It is paradoxical: fainting in the face of perceived danger. The syncope could be adaptive in certain dangerous situations, so as to survive as a younger adolescent. In primates, when fighting a stronger alpha male, it is adaptive to faint and then have a chance at survival.

  • Vasovagal syncope is observed in adolescents of other primate species.
  • Humans are sensitive to early stress or trauma. As with most behaviors, this is true for other species as well. Even fish are sensitive to early stresses! In primates the effects of stress begins in utero (if mom is stressed, cortisol changes result and this greatly affects the fetus). The vital amygdala-prefrontal cortex connectome is greatly influenced in utero and in the first year of life.
  • Aggressive and alpha behavior can be learned (as demonstrated by fish: the fish that lost the battle with an alpha fish, then was allowed to watch the alpha fish interact with others, subsequently learns to act like an alpha fish).
  • Taking an ethological (observing behavior in various species) approach, depression may be observed in most species.
  • These species include primates, voles, rats, and (There is an excellent YouTube talk on this: An Evolutionary Model of Depression, by Markus Rantala)
  • The pelvis changes that resulted from going bipedal contribute to our difficulty with childbirth. Human mothers have more childbirth pain than other species. Human infant and/or mother mortality has been 10 to 20%. The baby has to rotate and flip. Our large skull size also contributes to the childbirth difficulties. We are born relatively immature, as compared to other primates, partly due to our large head: we are born earlier than is ideal.