The Smallest Thing We Trust
“The good physician treats the disease; the great physician treats the patient who has the disease.” William Osler (physician)¹
It may be the most remarkable object in your home. Not your phone. Not your computer. Not even your car.
A pill.
Small enough to disappear beneath your fingernail, yet powerful enough to lower blood pressure, stop a seizure, replace a missing hormone, prevent a transplanted organ from rejecting a transplanted kidney, cure an infection that would once have been fatal, or quiet the emotional earthquake of bipolar disorder. Every morning, billions of pills are swallowed around the world with remarkably little hesitation. We rarely stop to wonder who first discovered them, how they were tested, who manufactured them, or why they work. We simply trust that somewhere, someone has already asked those questions for us.
That trust is extraordinary.
• Americans fill more than 6 billion prescriptions each year.²
• Nearly two-thirds of American adults take at least one prescription medication annually.³
• Adults over age 65 take an average of four to five prescription medications every day.⁴
For something so commonplace, pills occupy a surprisingly complicated place in our culture. We celebrate antibiotics without giving them much thought, yet argue endlessly about antidepressants. We admire someone who faithfully takes insulin while quietly wondering whether a person taking lithium or Adderall has somehow become “dependent.” Medications for the heart, lungs, kidneys, or thyroid rarely become moral questions, but medications that affect the brain often do. Somewhere between the pharmacy and the medicine cabinet, chemistry becomes philosophy.
As the physician and essayist Lewis Thomas observed, “The greatest of all the accomplishments of twentieth-century science has been the discovery of human ignorance.”⁵ Every generation has celebrated medicines that seemed almost miraculous. Penicillin transformed infections that had killed people for centuries. Insulin changed type 1 diabetes from a fatal disease into a chronic one. Vaccines nearly eliminated illnesses that once filled children’s hospitals. More recently, GLP-1 medications have changed the treatment of obesity, while ketamine has challenged decades of assumptions about severe depression.⁶ Now we are actually investigating psychedelics. The history of medicine is full of discoveries that initially seemed almost magical.
What interests me even more, however, is not the chemistry inside the pill but the meaning we attach to it.
As a psychiatrist, I spend surprisingly little time convincing patients that medications can work. Most people already believe that. The conversations are almost always about something else. Patients ask whether a medication will change their personality, whether they will need it forever, whether taking it means they have somehow failed, or whether they will stop feeling like themselves. Those are not pharmacological questions. They are questions about identity, responsibility, and what it means to remain ourselves while accepting help.
Those questions did not begin with Prozac or Adderall. They have accompanied medicine for thousands of years. To understand why we continue asking them, we have to begin long before pharmaceutical companies, clinical trials, or even pharmacies themselves. We have to return to ancient Egypt, where physicians wrapped bitter herbs in honey and dates, hoping patients would swallow remedies that sometimes worked, often didn’t, and almost always required faith.
The history of the pill turns out to be much more than the history of medicine. It is also the history of what human beings have always hoped medicine might become.
Honey, Dates, and Snake Oil
“The desire to take medicine is perhaps the greatest feature which distinguishes man from the other animals.” William Osler¹⁰
Long before there were pharmacists, there were healers. Long before there were prescriptions, there were recipes. And long before medicine became a science, it was an experiment repeated thousands of times by people who were simply trying to ease suffering with whatever nature happened to provide.
One of the earliest surviving medical texts is the Egyptian Ebers Papyrus, written around 1550 BCE. It contains more than seven hundred remedies for ailments ranging from intestinal parasites to skin diseases, breathing problems, fractures, and mental disturbances.¹¹ Egyptian physicians were remarkably sophisticated observers, but they faced the same problem every parent faces today.
How do you convince someone to swallow something that tastes terrible?
Their solution was wonderfully practical. Bitter herbs, powdered minerals, and other medicinal ingredients were mixed with honey or mashed dates, then rolled into small balls that could be swallowed whole. They were not pills in the modern sense, but they were close enough that the basic idea has survived for nearly four thousand years.
• The Ebers Papyrus contains more than 700 medicinal formulas.¹²
• Honey has been used medicinally for at least 4,000 years.¹³
• Ancient Egyptian physicians prescribed everything from willow bark to crocodile dung.
Fortunately, only one of those eventually became aspirin.
The Greeks inherited much of Egyptian medicine, and the Romans eagerly borrowed from the Greeks. Medieval apothecaries refined the art of preparing medicines, coating pills with sugar because patients then, just like patients now, preferred not to gag. Physicians gradually became better at recognizing which remedies appeared to help, but they usually had no idea why they worked. Medicine advanced by observation far more often than by understanding. Sometimes that approach led to genuine breakthroughs. Sometimes it led to centuries of bloodletting, mercury, arsenic, and treatments that probably harmed more people than they healed.
• Bloodletting remained a standard medical treatment for nearly two thousand years.
• Mercury was prescribed for everything from constipation to syphilis.
• Cocaine, heroin, cannabis, alcohol, and opium have all been sold legally as medicines.
As Lewis Thomas wrote, “Our triumphs are not in our understanding but in our noticing.”¹⁴ That sentence captures much of medical history. Long before anyone understood bacteria, neurotransmitters, or DNA, observant physicians occasionally noticed that certain treatments consistently seemed to help. They lacked explanations, but they had evidence, even if they didn’t yet know how to interpret it.
Unfortunately, uncertainty also creates opportunity.
By the nineteenth century, medicine had become one of the fastest-growing businesses in the world. If you owned a bottle, a printing press, and enough confidence, you could market yourself as a medical expert. Newspapers overflowed with advertisements promising relief from nervous exhaustion, melancholy, baldness, indigestion, alcoholism, “female weakness,” and almost every inconvenience associated with being alive. Many of those miracle cures contained generous amounts of alcohol, morphine, cocaine, or opium. Patients often reported dramatic improvement, which probably says as much about the ingredients as the advertising.
• Mrs. Winslow’s Soothing Syrup, marketed for teething infants, contained morphine.
• Bayer introduced heroin in 1898 as what was believed to be a safer alternative to morphine.
• Cocaine appeared in wines, toothache drops, tonics, and countless over-the-counter remedies before its dangers were fully understood.
Years ago, I became friends with Jim Hogshire, whose wonderfully eccentric collection of essays, Pills A-Go-Go, chronicles this era with equal parts fascination and disbelief. Reading those old advertisements today is like opening a pharmaceutical time capsule. The illustrations feel quaint, the language melodramatic, and the medical claims almost comically exaggerated. Then, after a few pages, something slightly uncomfortable happens.
You begin to recognize them. The fonts are different. The regulations are stricter. The television commercials are certainly better produced.
But the promise remains remarkably familiar. Yesterday’s advertisements offered stronger nerves, renewed energy, happier marriages, calmer children, and a better night’s sleep. Today’s advertisements promise sharper concentration, better sex, lower cholesterol, weight loss, smoother skin, and freedom from diseases most of us had never heard of until the commercial interrupted our favorite television show.
As George Carlin observed, “The reason they call it the American Dream is because you have to be asleep to believe it.”¹⁵ He wasn’t talking about pharmaceuticals, but he understood something about advertising. We have always wanted to believe that somewhere, someone has discovered the medicine that will not merely make us healthier, but make life itself a little easier.
Medicine gradually became a science. Selling medicine never stopped being an art.
Mother’s Little Helper
“There is no health without mental health.” David Satcher (former U.S. Surgeon General)¹⁶
By the middle of the twentieth century, medicine had entered an age that would have seemed miraculous to almost every physician who had come before it. Antibiotics cured infections that had once killed young adults in the prime of life. Vaccines emptied children’s hospital wards. Insulin transformed type 1 diabetes from a fatal diagnosis into a chronic illness. Surgery became safer. Life expectancy climbed. For perhaps the first time in history, physicians could reasonably expect many of their patients to recover.
Success changes expectations.
Once medicine demonstrated that it could cure disease, people naturally began wondering what else it might improve. If a pill could eliminate pneumonia, why couldn’t another make us less anxious? If one could stop seizures, perhaps another could sharpen attention. If chemistry could restore health, perhaps it could also make ordinary life a little easier to live.
That wasn’t simply wishful thinking. It became one of the most successful advertising campaigns in history.
• Miltown became the first blockbuster tranquilizer.
• By the early 1970s, Valium was among the most prescribed medications in the world.
• Amphetamines were widely marketed for weight loss, energy, and what advertisements cheerfully described as “pep.”
Looking back at those advertisements today is equal parts amusing and unsettling. Smiling women in pearls happily vacuumed the house, then served dinner because their “nerves” had finally settled down. Husbands returned home to cheerful wives. Children behaved. The kitchen sparkled. Reading them now, it is difficult not to wonder whether the medication was treating anxiety or simply making impossible expectations feel a little more tolerable.
No one captured that contradiction better than Mick Jagger and Keith Richards in the Rolling Stones’ 1966 song Mother’s Little Helper. The song is often described as being about Valium, but it is really about something much larger. It asks what happens when ordinary exhaustion, loneliness, boredom, and disappointment begin to look like medical problems waiting for pharmaceutical solutions.
That question has never gone away.
As Carrie Fisher once observed, “If my life wasn’t funny, it would just be true, and that is unacceptable.”¹⁷ Humor often notices cultural shifts long before medicine does. Comedians, musicians, and novelists had already begun asking whether we were drifting from treating illness toward treating the ordinary frustrations of everyday life.
• Cigarettes were once advertised by physicians.
• Coca-Cola originally contained cocaine and 7-Up once contained lithium.
• Heroin, cocaine, amphetamines, barbiturates, and benzodiazepines have all, at one time or another, been celebrated as modern medical breakthroughs.
It is tempting to laugh at those advertisements because they seem so obviously misguided. The danger is believing we have become immune to making similar mistakes. History has a way of humbling every generation. We shake our heads at Victorian patent medicines while confidently embracing today’s newest miracle drug, forgetting that our grandchildren may someday look back at our own advertisements with exactly the same mixture of amusement and disbelief.
That does not mean medicine has failed. Quite the opposite. Many of those medications remain enormously valuable when used for the right patient, in the right circumstance, and for the right reason. Amphetamines remain among the most effective treatments for ADHD. Benzodiazepines can be lifesaving during severe panic attacks, alcohol withdrawal, or acute agitation. Opioids remain indispensable after major surgery and in hospice care. The problem has never been the medications themselves.
The problem is that medicine is often asked to answer questions that are not entirely medical. Where does illness end and ordinary human suffering begin?
The grieving widow who cannot stop crying may not have major depression. The overwhelmed college student may not have ADHD. The exhausted parent juggling two jobs and three children may not have an anxiety disorder. At the same time, genuine depression, ADHD, and anxiety disorders are every bit as real as diabetes or asthma, and dismissing them as ordinary stress can be just as harmful as overdiagnosing them.
The line separating illness from the normal struggles of being human has never been as sharp as we would like it to be. Every generation redraws that line a little differently, influenced by new discoveries, changing social expectations, and sometimes by very effective advertising. That uncertainty has become one of medicine’s greatest challenges. It has also become one of psychiatry’s.
Medicine Is Part Chemistry, Part Theater
“The art of medicine consists of amusing the patient while nature cures the disease.” Voltaire¹⁸
At first glance, Voltaire’s observation sounds like a cynical dismissal of medicine. In fairness to him, he wrote those words nearly a century before physicians understood that bacteria caused infections and almost two centuries before antibiotics transformed modern medicine. Most of the treatments available in his lifetime were ineffective, and some were actively harmful. A wise physician often accomplished more by listening carefully, offering reassurance, and avoiding dangerous interventions than by prescribing the fashionable treatment of the day.
Oddly enough, modern medicine has brought us back to appreciating part of what Voltaire meant. Not because medicine doesn’t work. Because patients do.
One of the most fascinating discoveries in medicine is that expectation itself can influence biology. Researchers have repeatedly shown that patients who believe they are receiving an effective pain medication often experience genuine pain relief even when they have received an inert pill. Brain imaging demonstrates measurable changes in the same pain-processing regions activated by opioid medications. Patients with Parkinson disease may release dopamine simply because they believe they are receiving treatment. Even sham surgical procedures, performed as part of carefully controlled clinical trials, have occasionally produced improvements surprisingly close to those seen after the actual operation.¹⁹
• Placebo responses have been demonstrated in chronic pain, depression, anxiety, Parkinson disease, migraine, and irritable bowel syndrome.
• Brain imaging shows that expectation activates many of the same neural pathways influenced by active medications.
• Patients who expect treatment to help are, on average, more likely to improve.
The opposite is equally true. Patients warned that a harmless pill commonly causes headaches, nausea, or dizziness are substantially more likely to experience those symptoms, even when the pill contains no active medication. Physicians have a name for this phenomenon. It is called the nocebo effect. Expectations can relieve suffering, but they can also create it.
As Lewis Thomas wrote, “We are, perhaps, much more than we know.”²⁰ The brain is not simply observing treatment from a distance. It is participating in it, interpreting it, and, in some cases, amplifying it.
That realization changes the way we think about many controversial treatments. Homeopathy, for example, remains scientifically implausible because most preparations contain little or none of the original substance. Yet many patients sincerely report feeling better after taking it. Critics often interpret those reports as evidence that patients are foolish or easily deceived. I think that misses the more interesting question.
What else happened? Did someone spend an hour listening carefully instead of fifteen rushed minutes? Did the patient finally feel heard? Did hope replace despair? Did sleeping improve because anxiety diminished? Did the act of believing that recovery was possible encourage someone to exercise, reconnect with friends, or pay closer attention to nutrition?
None of those experiences violates biology. They are biology.
• Larger pills are generally perceived as stronger than smaller ones.
• Patients consistently rate injections as more powerful than pills, even when the medication is identical.
• The color of a pill can influence expectations, with blue tablets often perceived as calming and red tablets as stimulating.
Comedian Tim Minchin likes to remind audiences, “You know what they call alternative medicine that’s been proved to work? Medicine.” The joke lands because it contains an important truth. Treatments that repeatedly demonstrate effectiveness eventually become part of ordinary medicine. Yet modern medicine has taught us something equally important. The molecule inside the pill is only one part of the treatment. Trust matters. Empathy matters. Listening matters. Explaining matters. A physician’s confidence, a patient’s expectations, and the relationship between them can all influence the final outcome.
That realization has changed the way I practice psychiatry. Writing the prescription is often the easiest part of the visit. Helping patients understand why a medication is being prescribed, what it can realistically accomplish, what it cannot accomplish, and why I believe it is worth trying often takes considerably longer.
Perhaps that is because prescribing a medication is only partly about chemistry. The rest is about earning trust.
One Pill Is Almost Never Enough
“For every complex problem there is an answer that is clear, simple, and wrong.” H. L. Mencken (journalist)²¹
One of the questions I hear most often is wonderfully straightforward. “Can’t you just give me one medication?”
Patients usually ask it after I’ve explained that I’d like to add a second medication rather than increase the dose of the first. They assume I’m changing course because the original prescription somehow failed.
In fact, the opposite is often true.
One of the quiet revolutions in modern medicine has been the realization that complex illnesses rarely respond to simple solutions. Physicians once dreamed of finding a single “magic bullet” for every disease. Increasingly, we’ve learned that biology doesn’t organize itself that neatly. The heart, the immune system, the endocrine system, and especially the brain all depend on countless interacting pathways. Changing one of them may solve part of the problem while leaving several others untouched.
• More than half of patients treated for hypertension eventually require two or more medications.
• Modern HIV treatment relies on combinations of antiviral medications.
• Many cancers are now treated with carefully designed combinations of surgery, radiation, chemotherapy, immunotherapy, and targeted medications.
Psychiatry follows exactly the same logic.
Patients with bipolar disorder often ask why they need lithium and lamotrigine, or lithium and an antipsychotic, instead of one medication that simply treats “bipolar disorder.” The answer is that bipolar disorder is not one biological problem. Mania and depression involve overlapping but distinct neural circuits. Sleep, circadian rhythms, inflammation, genetics, stress hormones, and neurotransmitters all interact continuously. A medication that does an excellent job preventing mania may do very little for bipolar depression. Another may improve depression but provide little protection against mania. Combining them is not an admission of defeat. It is an acknowledgment of reality.
That way of thinking has quietly spread throughout medicine. HIV became a manageable chronic illness only after physicians stopped searching for a single miracle drug and began attacking the virus from several different directions at once. Cancer specialists routinely combine treatments because tumors adapt when confronted with only one. Infectious disease physicians prescribe multiple antibiotics for tuberculosis for exactly the same reason.
Medicine has become less interested in finding one perfect answer. It has become much better at finding combinations that work.
• The word “polypharmacy” simply means using multiple medications, although the term is often used when combinations become excessive or unnecessary.
• Evidence-based combination therapy is standard practice throughout cardiology, oncology, infectious disease, rheumatology, and psychiatry.
• The goal is never to prescribe more medications. The goal is to prescribe enough medications to solve the problem while creating the fewest new ones.
Of course, every additional medication increases the possibility of side effects, and that is where psychiatry often becomes frustrating for both physicians and patients. Some of our most effective antipsychotic medications dramatically improve psychosis while simultaneously increasing appetite, reducing insulin sensitivity, and altering metabolism. A patient may finally think clearly after years of hallucinations, only to gain sixty pounds over the following year.
Patients naturally ask why pharmaceutical companies cannot simply eliminate those side effects. The answer is that the receptors involved in thought, appetite, movement, sleep, and metabolism are not isolated from one another. Evolution recycled the same biological machinery over and over again. A receptor helping regulate mood in one part of the brain may also participate in hunger somewhere else. Alter one system and several others often respond.
That is one reason I find recent developments so interesting. Years ago, psychiatrists often prescribed metformin to reduce antipsychotic-associated weight gain. More recently, GLP-1 receptor agonists have shown even greater promise. We have reached the curious point where one medication is sometimes prescribed to reduce the side effects of another.
At first glance, that sounds absurd. In reality, it is exactly how medicine has always progressed. Every generation discovers that the body is more complicated than it first appeared, and every generation responds by developing more precise ways of working with that complexity. The goal has never been to prescribe more pills.
The goal has always been to help patients live better lives with as little medication as possible, but as much as necessary. That distinction becomes especially important when the medication affects the organ we associate with our very identity.
Will This Change Who I Am?
“The physician’s essential task is to recognize the patient’s humanity.” Oliver Sacks (neurologist)²²
If there is one question that separates psychiatry from nearly every other medical specialty, it is not whether the medication will work. It is whether the medication will change the person taking it.
Patients rarely ask a cardiologist whether a blood pressure medication will alter their personality. They don’t usually ask an endocrinologist whether insulin will make them feel like someone else. They may worry about side effects, cost, or inconvenience, but they seldom wonder whether treating diabetes or hypertension somehow changes who they are.
Psychiatry is different.
Not because psychiatric medications are uniquely powerful, but because they affect the organ we associate with memory, personality, humor, ambition, love, creativity, and consciousness itself. When patients agree to begin an antidepressant, stimulant, mood stabilizer, or antipsychotic, they are not simply trusting me with an illness. They are trusting me with what they experience as their very self.
• Nearly one in five American adults experiences a mental illness each year.
• Fear of “personality change” remains one of the leading reasons patients hesitate to begin psychiatric medication.
• Psychiatric medications remain among the most stigmatized treatments in medicine.
Those fears did not appear out of nowhere. For nearly a century our novels, movies, and television shows have warned us about medications that erase individuality. In Aldous Huxley’s Brave New World, people take soma not because they are sick, but because it keeps them comfortable, compliant, and unwilling to question society. Ken Kesey’s One Flew Over the Cuckoo’s Nest portrayed psychiatric hospitals as places where medication was used as much to control as to heal. Decades of films have reinforced the same image, depicting psychiatric medications as chemical restraints that flatten emotion and extinguish creativity.
It is hardly surprising that patients walk into my office wondering whether medication will turn them into someone they no longer recognize. What has always struck me is the irony. Untreated mental illness changes personality far more dramatically than most psychiatric medications ever do.
Depression steals curiosity long before it steals happiness. Friends notice that someone laughs less, withdraws from conversations, loses interest in hobbies, and stops returning phone calls. Anxiety gradually shrinks the boundaries of life until vacations, restaurants, airplanes, and even grocery stores begin disappearing from someone’s world. Obsessive-compulsive disorder replaces freedom with ritual. Bipolar disorder can transform a thoughtful, cautious person into someone who spends recklessly, sleeps two hours a night, destroys relationships, or believes they have become invincible. Schizophrenia can make reality itself unreliable.
By the time many patients arrive in my office, the illness has already been changing them for months, sometimes years. Treatment is an attempt to interrupt that process.
As Oliver Sacks spent his career reminding us, physicians treat diseases, but they care for people. I have never thought of my job as creating a new personality. If treatment is working well, patients rarely become different people. More often they begin sounding like the person their spouse remembers, the child their parents recognize, or the version of themselves they thought had disappeared. The woman whose depression had stolen her laughter laughs again. The teenager with ADHD finishes a conversation without drifting away halfway through a sentence. The man with panic disorder attends his daughter’s wedding instead of staying home because the thought of traveling had become unbearable.
Those moments rarely feel like transformation. They feel like restoration.
• Effective treatment for ADHD reduces accidental injuries, substance misuse, and motor vehicle accidents.
• Effective treatment for bipolar disorder lowers relapse rates, hospitalization, and suicide.
• Successfully treating depression often improves physical health as well as emotional well-being.
That perspective also explains why I answer another common question a little differently than patients expect.
“How long will I have to take this?”
People are often surprised when I respond with a question of my own.
“How long do you plan on having ADHD?”
Or bipolar disorder. Or schizophrenia.
It is not meant to be clever. It is meant to shift the conversation.
We do not ask how long someone should continue taking insulin for type 1 diabetes or when they can finally stop wearing eyeglasses. We understand that those treatments help people function in the presence of an ongoing condition. Psychiatric medications are no different. Some people take them for months. Others take them for decades. The decision is guided by the illness itself, not by an arbitrary calendar.
That does not mean everyone should remain on medication forever. Some conditions resolve completely. Others improve enough that medication can be reduced or discontinued. One of the most satisfying conversations I have with patients is deciding together that they no longer need something I once prescribed. Good psychiatry should always involve asking whether each medication is still necessary, not simply continuing it because it has become part of the routine.
As Viktor Frankl wrote, “Between stimulus and response there is a space. In that space is our power to choose our response.”²³ Severe mental illness narrows that space. Depression convinces people there is no future. Panic disorder persuades them there is no escape. Mania eliminates caution. Psychosis distorts reality itself. At its best, treatment widens that space again.
That is why I have never liked the expression “happy pills.” The goal of psychiatric medication is not to manufacture happiness or create artificial contentment. It is to reduce enough suffering that patients can begin making meaningful choices again, rebuilding relationships, pursuing work they enjoy, raising children, finding purpose, and reclaiming lives that illness had gradually taken away.
Perhaps that is the most important distinction in all of psychiatry. The best medications do not change who we are. They help us become ourselves again.
The Search Continues
“The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.” Sir William Lawrence Bragg (physicist and Nobel laureate)²⁴
If medicine has taught us anything over the past four thousand years, it is that certainty has an unusually short shelf life.
Egyptian physicians believed they understood disease. So did the Greeks. Medieval physicians confidently prescribed bloodletting. Nineteenth-century doctors embraced mercury, arsenic, cocaine, heroin, and countless patent medicines that promised miraculous results. Every generation has looked back at the one before it with a mixture of amusement and disbelief, convinced that modern science had finally separated fact from fantasy.
Then the next generation arrived.
That perspective has changed the way I think about psychiatry. Early in my career I thought of medications largely in terms of neurotransmitters. Increase serotonin. Decrease dopamine. Strengthen norepinephrine. The model was useful, and it remains useful today, but it also turns out to be incomplete. As our understanding of the brain has expanded, those familiar neurotransmitters have become part of a much larger story involving inflammation, genetics, circadian rhythms, neuroplasticity, immune signaling, the microbiome, hormones, and dozens of biological systems that interact in ways we are only beginning to understand.
• Most psychiatric medications were discovered before scientists understood precisely how they worked.
• There is still no laboratory test that diagnoses depression, bipolar disorder, schizophrenia, or ADHD. Certainly no imaging.
• Every one of those diagnoses almost certainly represents many different biological illnesses rather than a single disease.
That is one reason lithium has become even more interesting with age. When John Cade first introduced it in 1949, physicians knew it stabilized mood because they could see the results. Only decades later did researchers begin discovering that lithium appears to protect neurons, influence intracellular signaling, increase neurotrophic factors, and promote neuroplasticity. The medication had been quietly doing far more than anyone realized.
Ketamine followed a remarkably similar path. Developed as an anesthetic, it was never intended to become an antidepressant. Yet some patients with severe depression improved within hours rather than weeks, forcing psychiatrists to rethink assumptions that had gone largely unchallenged for decades. Today the leading theories suggest that ketamine may rapidly strengthen or restore synaptic connections damaged by chronic stress and depression rather than simply altering neurotransmitter levels.²⁵
• Lithium remains the only psychiatric medication consistently shown to reduce suicide risk in bipolar disorder.
• Ketamine can reduce depressive symptoms, including suicidal ideation, within hours in some patients.
• Exercise, sleep, psychotherapy, learning, and meaningful relationships all promote neuroplasticity.
That last observation may ultimately prove more important than either medication.
Patients often ask whether medication or psychotherapy works better, as though they are competing treatments. The brain makes no such distinction. A meaningful conversation changes the brain. So does learning a new language, recovering from grief, falling in love, exercising regularly, sleeping well, raising children, reading a book, or living through a pandemic. Every experience leaves fingerprints on the nervous system. Medication is not an alternative to those experiences. It is sometimes what makes them possible.
As neuroscientist Eric Kandel famously demonstrated, learning itself changes the structure of the brain.²⁶ Once you accept that idea, one of psychiatry’s oldest debates begins to dissolve. Medication versus therapy becomes medication and therapy. Biology and psychology stop competing because they were never separate in the first place. Every thought is biological. Every biological change influences thought.
Looking back over the history of medicine, I no longer think it is the story of humanity searching for the perfect pill. It is the story of humanity gradually learning how difficult healing really is. The more carefully physicians have studied the body, the less mysterious many diseases have become, but the more awe-inspiring the human organism has become in return. Every answer uncovers another layer of complexity. Every discovery opens an entirely new field of questions.
That is not discouraging. It is the reason medicine continues to move forward.
Perhaps there never will be a medication that cures every form of depression, prevents every psychotic illness, or eliminates bipolar disorder forever. Perhaps the future lies instead in understanding which combinations of medication, psychotherapy, exercise, nutrition, sleep, education, relationships, and purpose allow each individual brain to function at its best. That future is less glamorous than the search for a miracle drug, but it is probably far more realistic.
When I began writing this article, I thought it was going to be about pills. Somewhere along the way I realized it is really about trust.
Every time we swallow a medication we place enormous faith in generations of physicians, scientists, pharmacists, patients, and researchers who devoted their lives to understanding a tiny piece of human biology. They made remarkable discoveries, made spectacular mistakes, corrected many of them, and left the next generation with better questions than they inherited themselves.
That may be the real history of medicine. Not a story about magic. A story about curiosity. About humility. And about an enduring belief that tomorrow we may understand just a little more than we do today. For something small enough to disappear beneath a fingernail, that is a remarkable legacy.
Notes & Sources
William Osler. Aequanimitas, with Other Addresses to Medical Students, Nurses and Practitioners of Medicine. Philadelphia: P. Blakiston’s Son & Co., 1904.
IQVIA Institute. The Use of Medicines in the U.S. Annual reports.
U.S. Centers for Disease Control and Prevention (CDC), National Center for Health Statistics. Prescription medication use among U.S. adults.
Agency for Healthcare Research and Quality (AHRQ). Medication use among older adults.
Lewis Thomas. The Medusa and the Snail. Viking Press, 1979; and The Lives of a Cell. Viking Press, 1974.
John Cade. “Lithium Salts in the Treatment of Psychotic Excitement.” Medical Journal of Australia. 1949. See also contemporary reviews on lithium, neuroprotection, neuroplasticity, and suicide prevention.
The Ebers Papyrus, c. 1550 BCE.
Edward Kremers and Glenn Sonnedecker. Kremers and Urdang’s History of Pharmacy.
Liddell and Scott. A Greek-English Lexicon. Entry: pharmakon.
William Osler. “The desire to take medicine is perhaps the greatest feature which distinguishes man from the other animals.” Commonly cited from Aequanimitas and related writings.
Jim Hogshire. Pills A-Go-Go. Essays on pharmaceutical advertising, drug culture, and the history of medications.
David Satcher. U.S. Surgeon General’s reports on mental health.
Mick Jagger and Keith Richards. “Mother’s Little Helper.” Aftermath. The Rolling Stones, 1966.
Fabrizio Benedetti. Placebo Effects (Oxford University Press) and related research on placebo and nocebo mechanisms.
Tim Minchin. Public lectures and performances discussing evidence-based medicine and alternative medicine.
Oliver Sacks. The Man Who Mistook His Wife for a Hat and An Anthropologist on Mars.
Aldous Huxley. Brave New World. London: Chatto & Windus, 1932.
Ken Kesey. One Flew Over the Cuckoo’s Nest. Viking Press, 1962.
Sir William Lawrence Bragg. Scientific writings and lectures.
Eric Kandel. Principles of Neural Science (with colleagues), In Search of Memory, and related work on learning, memory, and neuroplasticity. See also Carlos Zarate Jr. and colleagues on ketamine in treatment-resistant depression, and recent reviews of GLP-1 receptor agonists for antipsychotic-associated weight gain.
Further Reading
David Healy. The Antidepressant Era.
Stephen M. Stahl. Stahl’s Essential Psychopharmacology.
Robert Whitaker. Anatomy of an Epidemic.
Jerome Groopman. How Doctors Think.
Atul Gawande. Complications and Better.
Siddhartha Mukherjee. The Emperor of All Maladies and The Gene.
Lewis Thomas. Late Night Thoughts on Listening to Mahler’s Ninth Symphony.
Oliver Sacks. Awakenings.
American Psychiatric Association Practice Guidelines.
Canadian Network for Mood and Anxiety Treatments (CANMAT) Guidelines.
U.S. Food and Drug Administration historical archives on patent medicines and the Pure Food and Drug Act of 1906.
I agree. Informed consent is not optional, and the possibility of a nocebo effect does not give a clinician permission to leave out meaningful risks. My point is about how those risks are communicated, not whether they are communicated. There is a difference between saying, “This medication can cause nausea, dizziness, insomnia, sexual dysfunction, weight gain…” as a frightening inventory of everything that might go wrong, and putting those same risks into context: how common they are, how serious they are, what we would do if they occurred, and why I still think the potential benefit makes the treatment worth considering. The patient needs the information before deciding. But informed consent does not require us to deliver that information in a way that inadvertently primes the patient to expect harm. If anything, the nocebo literature makes the consent conversation more important, not less.
You end the nocebo passage wider than the inert-pill research, on expectation itself. The consent conversation before a drug gets started falls under that sentence too. Relevant risks have to be said out loud before the patient decides, whatever the saying does to what comes next. Which is the part of the explaining nobody gets to leave out.
When the essay reaches your own visits, what you describe explaining is why the drug is being prescribed and why you think it's worth trying.
Same in surgical consent. The risk gets named before the decision.