It used to be that getting older meant slowing down. A little less pep, a little less zip, a little less zest. So it goes.

For men, this was partly about testosterone. After 40 or so, our bodies produce less and less testosterone, the hormone that helps give men energy and vigor and sex drive. Lower testosterone was just part of growing older.

But that was then! Nowadays, ?Low T? is a bonafide medical condition - easily treated with a shot at your local neighborhood men?s health clinic.

Today, what used to be a secret sauce of bodybuilders or cheating athletes is now downright normal. Millions of men worldwide take testosterone therapy - and not just those over 40. Check out Reddit or TikTok...It is a WHOLE THING.

In this episode of Drug Story, we look at how TRT went mainstream, and how part of ordinary aging somehow became a disease.

Sources for this episode

[1] Male Hypogonadism (2024) STAT Pearls:Male hypogonadism is defined as inadequate testosterone production or impaired spermatogenesis, diagnosed via symptoms and low morning testosterone levels.

[2] Brown-Séquard: An improbable genius who transformed medicine (2011) The Journal of Clinical Investigation: Charles-Edouard Brown-Séquard, a pioneering 19th-century scientist who rose from a difficult childhood in Mauritius is said to be the founder of modern endocrinology and neurology.

[3] The life and legacy of Brown-Séquard (2017) Brain: Charles-Edouard Brown-Séquard?s insights helped show how nerves control blood vessels and laid the foundation for modern endocrinology by identifying internal secretions and early hormone therapy.

[4] The ?Elixir of Life? (1889) J.G. Cupples Co: In a self-report, Charles-Édouard Brown-Séquard covers his controversial self-experiments where he injected animal testicle extracts in pursuit of rejuvenation.

[5] The effect produced on man by subcutaneous injections of a liquid obtained from the testicles of animal (1889) Lancet: In a 1889 Lancet article, Brown-Séquard describes his pioneering experiments with subcutaneous injections of animal testicular extracts to combat the physical and mental decline associated with aging.

[6] A Brief History of Testosterone (2001) Journal of Urology: Hormone therapy became widely used to treat age and disease-related hormone decline, before risks were fully understood.

[7] History of Testosterone and Therapeutic Potential (2020) Sexual Medicine Reviews: Testosterone was isolated in 1935 by the Organon group, with independent synthesis by Adolf Butenandt and Leopold Ruzicka.

[8] Adolf Butenandt?Nobel Prize for Chemistry (2012) Mayo Clinic Proceedings: Adolf Butenandt isolated key sex hormones, contributing to foundational methods for steroid chemistry and earning the 1939 Nobel Prize in Chemistry.

[9] Monkey business: reflections on testosterone (2012) BMJ: Testosterone is widely believed to drive masculinity, aggression, and performance, but strong evidence in humans is limited and inconsistent.

[10] The male hormone (1945) Harcourt, Brace and Company: The Male Hormone was an influential book that shaped public and medical perceptions of testosterone as central to masculinity and male health.

[11] Endocrines: The Use of Testosterone (1940) The New England Journal of Medicine: Dr. Joseph C. Aub?s NEJM article discusses testosterone as proven therapy for hypogonadism, with experimental applications for women and other conditions.

[12] History of Doping in Sport (2001) International Sports Studies: Testosterone and anabolic steroids became central substances in performance enhancement, prompting regulatory responses and anti-doping frameworks in international sport.

[13] New 'Breakfast of Champions': A Recipe for Victory or Disaster? (1988) The New York Times: Anabolic steroid use, including testosterone derivatives, was widespread in elite athletics despite known health risks and weak enforcement.

[14] FTC Sues Drug Companies for Unlawfully Conspiring to Delay the Sale of Generic AndroGel Until 2015 (2009) Federal Trade Commission: Pharmaceutical companies used patent litigation and settlement agreements to delay generic testosterone gel competition and maintain market exclusivity.

[15] Androgen deficiency in males (2010) Expert Review of Endocrinology & Metabolism: Clinical definitions of androgen deficiency rely on serum testosterone thresholds combined with symptoms, with variability across populations.

[16] The male menopause?does it exist? (2000) BMJ: Age-related testosterone decline occurs gradually and inconsistently and does not parallel the hormonal cessation observed in female menopause.

[17] Evolution of Guidelines for Testosterone Replacement Therapy (2019) Journal of Clinical Medicine: Article examines how definitions, diagnoses, treatments, and follow-up recommendations for testosterone replacement therapy have evolved across major societies (ISSAM, Endocrine Society, ISSM, AUA).

[18] The Hazards of Male Menopause (1997) Science: Medicalization of age-related testosterone decline outpaced clinical evidence, raising concerns about overtreatment and long-term risk.

[19] Selling That New-Man Feeling (2013) The New York Times: Direct-to-consumer advertising reframed testosterone therapy as a solution for fatigue, low mood, and diminished masculinity in aging men.

[20] Prevalence of hypogonadism in males aged at least 45 years: the HIM study (2008) The International Journal of Clinical Practice: A study established low measured testosterone levels prevalent among men over 45, particularly in those with obesity, diabetes, and chronic illness.

[21] Testosterone Aids Older Men's Brains, UCSF Study Says (2002) Science Daily: Testosterone supplementation was associated with short-term improvements in certain cognitive measures in older men.

[22] Association Between Direct-to-Consumer Advertising and Testosterone Testing and Initiation in the United States, 2009?2013 (2017) JAMA: A study finds increased exposure to testosterone advertising correlated with higher rates of testosterone testing and treatment initiation.

[23] 2013 All-Star Large Pharma Marketing Team of the Year: AndroGel (2013) Medical Marketing and Media: AndroGel?s marketing strategy successfully expanded testosterone therapy into a high-revenue lifestyle pharmaceutical category.

[24] The marketing of testosterone treatments for age-related low testosterone or 'Low T' (2018) Current Opinion in Endocrinology & Diabetes and Obesity: Discusses how pharmaceutical companies promoted testosterone for off-label, age-related use without strong supporting evidence.

[25] ?Manopause?! Aging, Insecurity and the $2 Billion Testosterone Industry? (2014) TIME: Highlights how clinics like Low T Centers exploit aging men?s fears and market testosterone as a cure-all for aging.

[26] ?More Men Are Seeking Out Testosterone Tests. Are They Getting Duped?? (2022) The New York Times: Reports on rising interest in testosterone testing and treatment, often marketed through online platforms targeting fatigue and low sex drive.

[27] FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use (2025) U.S. Food & Drug Administration: Testosterone products were required to update labeling to reflect increased risks of heart attack and stroke and to limit use to clinically verified hypogonadism.

[28] The Virility Paradox (2018) Simon & Schuster: Testosterone has a wide influence on human behavior, health, culture, and society, shaping traits from strength and drive to aggression and selfishness.

[29] The Testosterone Myth (2018) WIRED: Article explores the widespread but unfounded belief that testosterone can reverse aging and restore vitality.

[30] Effects of Testosterone Treatment in Older Men (2016) New England Journal of Medicine: In men 65 and older with low testosterone, raising levels of testosterone improved sexual desire and activity and had modest effects on mood and physical function, but did not improve vitality or walking distance.

[31] Promoting ?Low T: A Medical Writer?s Perspective (2013) JAMA Internal Medicine: A former ghost writer for the Low T campaign reveals how they got their message out in "educational" materials and articles.

Do you feel that?

That doubt and dread and worry?

That?s anxiety - and lucky for you, there?s a pill for that.

It?s called Xanax. And it works. Really well. And really fast.

Prescribed for panic attacks and anxiety, one dose of Xanax usually kicks in within 15 or 30 minutes. Just like that, a sense of calm sets in, and your concerns fall away. It?s not a high, more like the opposite. You feel relaxed, your brain stops racing. It does the trick.

Which is why Xanax is also super dangerous. Because of how well it works, and the way it works, Xanax is highly addictive. It brings such relief that one pill every once in a while turns into a little nibble every night. It tricks people into thinking that their concerns and worries can disappear with just one dose. Which is why Xanax is among the most counterfeited and abused drugs in the world right now.

Writing this episode, I started thinking that Xanax was a perfectly fine drug that is sometimes a problem. But as I dug in, I realized that Xanax, like all benzodiazepines, is a trickster. It promises to be an easy, even fun way to push our anxiety aside. But as much as it brings relief, it also brings consequences - which can turn deadly.

In this episode of Drug Story, we look at the idea of anxiety as a disease - a common human problem that can become, for some, a treatable condition. And we consider what ?treatment? means, for good and for bad.

Sources for this episode

[1] Quitting Xanax: One Writer's Story (2024) Vogue Magazine: Martha McPhee details her seventeen-year dependence on Xanax, originally prescribed for panic attacks.

[2] Fear and fitness: An evolutionary analysis of anxiety disorders (1994) Ethology and Sociobiology: Anxiety evolved as a defense mechanism with subtypes adapted to specific threats; anxiety disorders arise from dysregulated defenses.

[3] A history of anxiety: from Hippocrates to DSM (2022) Dialogues in Clinical Neuroscience: Traces the understanding and classification of anxiety from ancient Greek and Roman philosophy to the DSM, noting Greco-Roman recognition of anxiety as a medical condition and early cognitive-behavioral approaches.

[4] Should You Be Upset? Cicero on the Desirability of Emotion (2022) Antigone Journal: Examines Cicero?s views on whether suppressing or embracing emotions is desirable.

[5] Cicero and the state-trait theory of anxiety: Another case of delayed recognition (1983) American Psychologist: H.J. Eysenck argues Cicero anticipated the modern distinction between anxious temperament and temporary anxious states.

[6] The Effects of Stoic Training and Adaptive Working Memory Training on Emotional Vulnerability in High Worriers (2021) Cognitive Therapy and Research: Results from a study show that practicing Stoicism significantly reduces rumination and boosts self-efficacy.

[7] Seneca (2024) Stanford Encyclopedia of Philosophy: Lucius Annaeus Seneca was a Roman philosopher who shaped stoicism and contributed to the concept of mindfulness and use of the present to manage emotions. 

[8] The developmental origins of anxiety (2004) Nature: Early developmental mechanisms establish a predisposition to anxiety through the interplay of genetic and environmental factors. While anxiety is a biological adaptive response to danger it becomes pathological when interfering with normal life. 

[9] DSM-III and the transformation of American psychiatry: a history (1993) The American Journal of Psychiatry: American psychiatry transitioned from a biopsychosocial model to a research-based medical model following the publication of the Diagnostic and Statistical Model.

[10] The Feminine Mystique (1963) National Humanities Center: In her 1963 seminal writings, Betty Friedan wrote about a pervasive dissatisfaction and feeling of emptiness among American housewives.

[11] Barbiturates: A Blessing and a Menace (1947) Journal of the American Pharmaceutical Association: A 1947 journal article aptly describes the nature of barbiturates as both a blessing and menace describing their medical importance as sedatives and their ability to be misused. 

[12] Listening to the Past: History, Psychiatry, and Anxiety (2005) The Canadian Journal of Psychiatry: 19th?early 20th century treatments for anxiety included the use of bromides, alcohol, opiates, and later barbiturates for relief.

[13] How Was Anxiety Treated in the 1900s? (2023) Connect by ManagedMinds: Historically, anxiety has been treated by asylums, rest cures, early psychotherapy, and modern psychiatric medications like SSRIs.

[14] The history of benzodiazepines (2013) The Consultant Pharmacist: Leo Sternbach discovered one of the first benzodiazepines, Valium, in 1955.

[15] The Launch of Xanax (1989) Drug Information Journal: Upjohn Company ran a successful marketing strategy using targeted psychiatrist outreach and consistent messaging to establish Xanax?s market position.

[16] Listening to Xanax (2012) New York Magazine: This article explores ?functional anxiety? in high-achieving urban professionals and Xanax?s role.

[17] The Great American Xanax Legacy (2018) VICE: Xanax has become a force in modern culture including hip-hop music where the brand drug is commonly name dropped and featured in songs. 

[18] The APA Task Force report on benzodiazepine dependence, toxicity, and abuse (1991) The American Journal of Psychiatry: Benzodiazepines are rarely abused alone but are often used alongside alcohol or opioids in substance abuse.

[19] F.D.A. Requires Stronger Warning Label for Xanax and Similar Drugs (2020) The New York Times: In 2020, the Food & Drug Administration added a warning label to all benzodiazepines cautioning against misuse and abuse of the drug.

[20] Balancing the Risks and Benefits of Benzodiazepines (2021) JAMA: Reviews benefits, risks, and strategies for rational prescribing following FDA labeling changes.

[21] FDA Drug Safety Communication  (2020) The U.S. Food & Drug Administration: FDA warning to highlight risks of abuse, addiction, dependence, and withdrawal for all benzodiazepines.

[22] A Review of Alprazolam Use, Misuse, and Withdrawal (2018) Journal of Addiction Medicine: There is high misuse liability of alprazolam and more severe withdrawal compared to other benzodiazepines.

[23] Alprazolam: Good for Some, Not Good for All! (2023) Journal of Clinical Psychopharmacology: Alprazolam poses high risk for addiction and difficult withdrawal given its pharmacological properties. 

[24] Benzodiazepine use, abuse, and dependence (2005) The Journal of Clinical Psychology: While there are few addiction cases from prescribed use of benzodiazepines, pharmacologic dependence can occur with long-term therapy.

[25] Benzodiazepine Tapering American Society of Addiction Medicine: Clinical guidelines recommend gradual tapering when discontinuing benzodiazepines.

For decades, obesity was treated as a matter of self-control and free will: If you were fat, it was your own fault.

You could try a diet - but the diet companies were also in on the fix: For years, Weight Watchers was owned by Heinz food ? and Jenny Craig was owned by Nestle. 

But it was still up to you. You made your choices, and you had to live with them. And so the obesity rate in the US soared from around 15% of the population in 1970 to more than 40% today. Clearly something is going on other than free will and personal choices.

In this episode of Drug Story, we explore the origins of the obesity epidemic: the Green Revolution in agriculture, which saved a billion lives, but also made grain cheap cheap cheap. And we look at what happened when the tobacco companies decided to diversify into the food business (surprise: food became a lot more addictive, and a lot less healthy). 

And we re-consider the whole idea of personal freedom and free will.

This episode's drug is Ozempic, and the whole class of GLP-1s that have up-ended our presumptions around obesity. These drugs have transformed millions of lives - they are surely one of the most impactful medical discoveries of the century. 

Unfortunately, these drugs have not dispelled the stigma around obesity. They?ve just shifted it a bit. If you think taking a GLP-1 is ?cheating,? you?re still stuck in the old blame game.

Sources for this episode

[1] KFF Health Tracking Poll May 2024: The Public?s Use and Views of GLP-1 Drugs (2024) KFF: KFF poll showing awareness, perceptions, and use of Ozempic, Wegovy, and similar medications in the U.S.

[2] Norman Borlaug Man Of The Year 1969 (2011) The International Maize and Wheat Improvement Center: Norman Borlaug introducing himself as a man who grew up during the Great Depression and was raised on a farm in Iowa. 

[3] Norman Borlaug and the Green Revolution (2017) 20th Century Time Machine: Norman Borlaug created a high-yield wheat strain that transformed the agricultural industry and saved an estimated one billion lives. Considered the father of the Green Revolution, he was awarded the Nobel Peace Prize in 1970.

[4] Chapter 1 | The Man Who Tried to Feed the World (2020) American Experience PBS: Norman Borlaug, inspired by his own upbringing in struggling Iowa, helped the world avoid famine and hunger through revolutionizing wheat production.

[5] Food Timeline FAQs: historic food prices (2024) Food Timeline: In addition to increasing the supply of food globally, the Green Revolution also made food much more affordable.

[6] What Is the Evidence for ?Food Addiction?? A Systematic Review (2018) Nutrients: A systematic review of 52 studies concludes that food addiction is a valid diagnostic construct that is more similar to substance use disorder than behavioral addiction, especially among processed foods with added sweeteners and fats.

[7] The Origins of the Obesity Epidemic in the USA?Lessons for Today (2022) Nutrients: The origins of obesity can be traced back to the introduction of ultra-processed food in the American diet. 

[8] US obesity rates have tripled over the last 60 years (2025) USA Facts: American rates of obesity have tripled since the 1960s, with over 40% of Americans having obesity.

[9] Daily supply of calories per person (2025) Our World in Data: From 1970 to 2020, Americans increased their daily calorie intake from about 3,000 to over 3,800 calories.

[10] US tobacco companies selectively disseminated hyper-palatable foods into the US food system: Empirical evidence and current implications (2024) Addiction: In a study reviewing industry documents and U.S. Department of Agriculture data from 1988 to 2002, food produced U.S. Tobacco companies that owned food companies were 80% more likely to be high in carbs and sodium than other foods.

[11] Many of today?s unhealthy foods were brought to you by Big Tobacco (2023) University of Michigan Department of Psychology: Research shows how major tobacco companies exerted their influence on the American diet by applying their expertise in chemical dependency to the food industry.

[12] Ultra-processed Food Consumption in Youth and Adults: United States, August 2021?August 2023 (2025) CDC: According to the CDC, ultra-processed foods are hyperpalatable, high in sodium, and low in fiber, like sandwiches, sweet bakery products, and sweetened beverages.

[13] Highly processed foods can be considered addictive substances based on established scientific criteria (2022) Addiction: Using the same scientific criteria the U.S. Surgeon General employed in 1988 to identify tobacco as addictive, this analysis suggests that highly processed foods, rich in refined carbs and added fats, should be considered addictive.

[14] Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake (2019) Cell Metabolism: In a randomized control trial, researchers discovered that participants on an ultra-processed diet voluntarily consumed about 500 extra calories per day. The study concludes that people gain weight on ultra-processed diets and lose weight on unprocessed ones.

[15] Cereal, pasta, and other food companies blast the FDA for a too-strict definition of ?healthy? (2023) STAT: The FDA has posed new rules on what can be considered ?healthy? for a food product, limiting added sugar, sodium, and saturated fats. Industry giants argue that these rules are overly restrictive and food will be less palatable to consumers if less sugar and salt is in food.

[16] Adult obesity rates rise in 6 states, exceed 35% in 7 (2018) American Medical Association: The American Medical Association reports that adult obesity rates in the United States have reached historic highs, now affecting nearly 40 percent of the population.

[17] Recognition of Obesity as a Disease H-440.842 (2023) American Medical Association: The American Medical Association recognized obesity as a disease in 2013.

[18] Obesity as a Disease: Has the AMA resolution had an impact on how physicians view obesity? (2016) Surgery for Obesity and Related Diseases: Even after obesity was classified as a disease in 2013, many providers remained unaware of the resolution or held conflicting views on its validity, and debated whether obesity is a primary pathology or merely a behavioral risk factor.

[19] The Story of GLP-1: Episode 4 - "The next really good idea". (2022) Novo Nordisk Foundation: Novo Nordisk executives convinced their CEO that obesity should be treated as a medical challenge rather than a cosmetic issue. 

[20] What the Scientists Who Pioneered Weight-Loss Drugs Want You to Know (2023) WIRED: Interview with Jens Holst and Joel Habener, pioneers of GLP-1 research and early development of this drug class.

[21] We Know Where New Weight Loss Drugs Came From, but Not Why They Work (2023) The New York Times: This article discusses unknowns in GLP-1 mechanism of action, their effects on brain hormone levels, and the reframing of obesity as a biological rather than moral condition.

[22] The Ozempic Era Could Shift Blame for Obesity From Individuals to Commercial Food Systems (2025) Issues in Science and Technology: Given GLP-1?s mechanism of action, which targets biological pathways in the brain, obesity can be understood as a consequence of ultra-processed foods and an industrialized food system rather than a failure of individual willpower; the authors draw parallels to the alcohol and tobacco industries.

[23] Jim Gaffigan's Laughs Through His Weight-Loss Journey | Hulu (2025) Hulu: Jim Gaffigan addresses the stigma of using weight-loss drugs, highlighting how critics accuse him of "cheating" while he views the medication as a necessary tool for a "guy trying to not die".

[24] PEP Stock | PepsiCo Inc. Q1 2025 Earnings Call (2025) AlphaStreet: In a 2025 earnings call, the CEO of PepsiCo reports on the need to manage and adapt to recent health trends, including the rise and adoption of GLP-1s, which have resulted in customers eating smaller portions.

There?s no blood test for depression, no MRI or CT scan that can detect it. Because depression, like a lot of things involved with mental health, is invisible. 

Still, depression is the most common mental health issue in the US and worldwide. Nearly 30% of Americans will be diagnosed with depression in their lifetimes.

Many people wind up taking an antidepressant. You?ve probably heard of these drugs by their brand names: Prozac Lexapro, Paxil and - the drug in this episode - Zoloft.

These drugs do help, but finding the right drug that works for the right person can take a lot of time, and a lot of trial and error. This can be a messy and frustrating process.

In this episode of Drug Story, we jump into that mess. We explore the mystery of how these drugs actually work - and why depression seems so much more common today than in the past.

Sources for this episode:

[1] History of depression through the ages (2020) Archives of Depression and Anxiety: From Hippocrates? humoral theory to Freud, key historical figures shaped the understanding and treatment of depression.

[2] History of Depression (2015) The Oxford Handbook of Mood Disorders: Symptom-focused diagnosis and treatment have contributed to the medicalization of normal human sadness.

[3] Minnesota Multiphasic Personality Inventory (2023) StatPearls: Developed in the 1930s and published in 1942, the Minnesota Multiphasic Personality Inventory (MMPI) is the most common psychometric test for assessing personality traits and psychopathology including depression.

[4] The development of Minnesota Multiphasic Personality Inventory (1994) Journal of the History of the Behavioral Sciences: Two scientists at the University of Minnesota, Starke Hathaway and J. C. McKinley, developed the MMPI in the 1930s, a widely adopted survey measuring mental illness.

[5] Depression as a disease of modernity: Explanations for increasing prevalence (2012) Journal of Affective Disorders: Modern lifestyle factors like poor diet, inactivity, and social isolation may contribute to rising depression rates.

[6] The creation of the concept of an antidepressant: An historical analysis (2008) Social Science & Medicine: The term antidepressant gained traction in the 1950s-1960s, framing drugs as disease-specific treatments for depression.

[7] A RATING SCALE FOR DEPRESSION (1960) Journal of Neurology, Neurosurgery & Psychiatry: Max Hamilton published the Hamilton Rating Scale for Depression (HAM-D) questionnaire to measure severity of depression symptoms.

[8] The PHQ-9 (2001) Journal of General Internal Medicine: The Patient Health Questionnaire (PHQ-9) is a nine-item depression symptom questionnaire used to screen adults for depression. Kurt Kroenke developed the PHQ in the mid-1990s with funding from Pfizer. 

[9] The Origin Story of the Zoloft Sad Blob, a Clinically Depressed Icon (2021) Mel Magazine: Early 2000s ads used a blob character to represent depression, which drew both praise and criticism.

[10] Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature (2005) PLoS Medicine: SSRIs are marketed as correcting a serotonin deficiency, despite a lack of conclusive scientific evidence.

[11] Antidepressants Don?t Work the Way Many People Think (2022) The New York Times: Experts note that the chemical imbalance theory of depression is outdated.

[12] Development of the commercial process for Zoloft®/sertraline (2005) Chirality: Continuous chromatography enabled efficient large-scale production of sertraline.

[13] The Architect of Zoloft (2015) Reed Magazine: Kenneth Koe modified tametraline compounds to block serotonin reuptake, leading to sertraline hydrochloride?s release as Zoloft in 1992.

[14] ACS Award for Team Innovation (2006) Chemical & Engineering News: Zoloft?s discovery was led by Pfizer scientists Reinhard Sarges, B. Kenneth Koe, Willard M. Welch, Albert Weissman, and Charles A. Harbert.

[15] Sertraline versus other antidepressive agents for depression (2010) Cochrane Database of Systematic Reviews: Sertraline is a selective serotonin reuptake inhibitor (SSRI) used as a first-line treatment for major depression, with evidence demonstrating superior efficacy over other antidepressants.

[16] Do Antidepressants Work? (2018) The New York Times: In multiple meta-analyses of antidepressant trials, researchers confirm that while antidepressants are more effective than placebos for treating acute major depression, the actual clinical benefits are mostly modest. Study design, participant selection, and publication bias may result in more favorable evidence supporting the use of antidepressants.

[17] What Obesity Drugs and Antidepressants Have in Common (2023) The New York Times: Aaron Carroll writes that because science cannot fully explain the biological mechanisms of mental health and obesity drugs, these treatments are stigmatized and incorrectly viewed as a lack of willpower rather than medically necessary.

[18] The STAR*D study: treating depression in the real world (2008) Cleveland Clinic Journal of Medicine: The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial established that 70% of patients with clinical depression could achieve remission using antidepressants after following a four-step sequence of switching various treatments until they found relief. 

[19] The STAR*D Trial: It Is Time to Reexamine the Clinical Beliefs That Guide the Treatment of Major Depression (2015) The Canadian Journal of Psychiatry: A reexamination of The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial argues the original findings from the study were overestimated due to poor study design and bias.

[20] Restoring STAR*D: A Reanalysis of Drug-Switch Therapy After Failed SSRI Treatment Using Patient-Level Data with Fidelity to the Original STAR*D Research Protocol (2025) medRxiv: A reanalysis of the STAR*D data found that switching antidepressants provides minimal benefit and has a higher risk-to-benefit ratio than stated in the original trial.

[21] Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials? (2008) Philosophy, Ethics, and Humanities in Medicine: An analysis of antidepressant data submitted to the FDA reveals selective reporting and publication bias that mask negative results, leading to an inflated perception of drug benefits.

[22] Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts (2019) American Psychological Association: Evidence-based recommendations for treating depressive disorders in children, adults, and older adults.

[23] Predictive biomarkers could ease the exhaustive trial-and-error of antidepressants (2023) STAT: Research aims to identify biomarkers to reduce the trial-and-error of antidepressant prescribing.

[24] AI Tool Matches Patients to Effective Antidepressants Faster (2024) Neuroscience News.com: Platforms like MeAgainMeds.com aim to reduce trial-and-error in finding effective antidepressants.

[25] More treatment but no less depression: The treatment-prevalence paradox (2022) Clinical Psychology Review: Despite advances in treatment, depression prevalence has not decreased since the 1980s.

[26] How Sertraline (Zoloft) Completely Changed My Life (2024) @itsblakematthew: Blake Matthews details his experience with Zoloft.

Once you turn 40, it seems like half the people you know are taking a statin drug. You know, because their cholesterol is high, and to prevent heart disease down the line. It makes sense: better safe than sorry.

This is a huge triumph for preventive medicine. Statin drugs have saved (or improved) the lives of millions of people because they acted early. This is how medicine (and public health) is supposed to work.

But the devil is in the details. Like all drugs, statins have side effects. And when they are prescribed for many millions of people, the math means that millions of people will not, in fact, get any benefit from the drug. It turns out that atorvastatin (and other statin drugs) may be the most over-prescribed drugs in the history of medicine. And therein lies a Drug Story.

Sources for this episode:

[1] Akira Endo- Gairdner Gala Acceptance Speech (2017) Canada Gairdner Awards: Akira Endo, the Japanese biochemist who discovered the first statin, reflects on American dietary and lifestyle habits that inspired him to develop a solution to prevent heart disease.

[2] Influence of nicotinic acid on serum cholesterol in man (1955) Archives of Biochemistry and Biophysics: Since 1955, the B-vitamin niacin (nicotinic acid) has been used in the treatment of high cholesterol.

[3] Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations (2024) JAMA Internal Medicine: The Predicting Risk of Cardiovascular Disease Events (PREVENT) cardiovascular risk equation excludes race, adds kidney function and statin use, and suggests fewer adults may be eligible for statins compared to pooled cohort equations.

[4] It Took A Brilliant Marketing Campaign To Create The Best-Selling Drug Of All Time (2011) Business Insider: Lipitor became the best-selling drug of all time through aggressive marketing to doctors and coinciding with the FDA?s allowance of direct-to-consumer drug advertising in 1997.

[5] Learning From Our Parents? Heart Health Mistakes (2017) The New York Times: Indigenous South Americans, the Tsimane, have low rates of coronary artery disease and healthier lifestyles compared to Americans, offering a model for prevention.

[6] CHOLESTEROL: DRUG HAILED AS TREATMENT BREAKTHROUGH (1987) The New York Times: The New York Times introduces lovastatin, a novel drug predicted to revolutionize the treatment of high cholesterol.

[7] Millions fewer people may need statins, a new study suggests. But guidelines have yet to agree (2024) STAT: The number of adults recommended for statins could drop from 45.4 million to 28.3 million based on new risk calculations.

[8] A historical perspective on the discovery of statins (2010) Proceedings of the Japan Academy: Akira Endo?s discovery of compactin from fungal cultures led to lovastatin, the first commercial statin.

[9] The Role of Lipids and Lipoproteins in Atherosclerosis (1950) Science: John Gofman discovered LDL cholesterol and its correlation with atherosclerosis through ultracentrifugation of plasma lipoproteins.

[10] Statins for Primary Cardiovascular Disease Prevention: Time to Curb Our Enthusiasm (2022) JAMA Internal Medicine: Cardiologists question the benefit of statins for individuals with low cardiovascular disease risk, citing limited evidence.

[11] History of the Framingham Heart Study (1957) Framingham Heart Study: The Framingham Heart Study identified key cardiovascular risk factors, including high cholesterol, blood pressure, smoking, obesity, diabetes, and inactivity.

[12] ?For Me There Is No Substitute?: Authenticity, Uniqueness, and the Lessons of Lipitor (2010) American Medical Association Journal of Ethics: Lipitor backlash followed when it was revealed that Dr. Robert Jarvik, spokesperson in Lipitor ads, was not licensed to practice medicine and misrepresented his credentials.

[13] Lipitor a story of rags to riches (2011) Arkansas Democrat-Gazette: Lipitor achieved success by lowering LDL cholesterol more effectively than competitors, aided by expanded statin eligibility guidelines.

[14] History in medicine: the story of cholesterol, lipids and cardiology (2021) e-Journal of Cardiology Practice: Cardiology research has an extensive history: from its identification in gallstones in 1769 to Nobel Prize-winning discoveries on lipids and atherosclerosis.

[15] Discovery of Lipitor (2009) Triumph of the Heart: The Story of Statins: Despite being the fifth statin introduced, Lipitor dominated the market due to superior LDL-lowering efficacy.

[16] Counting Cholesterol (1987) The MacNeil/Lehrer NewsHour: Merck?s Mevacor became the first FDA-approved statin and cholesterol-lowering drug.

[17] Cardiovascular Disease Resulting From a Diet and Lifestyle at Odds With Our Paleolithic Genome: How to Become a 21st-Century Hunter-Gatherer (2004) Mayo Clinic Proceedings: High cholesterol may stem from a mismatch between modern diets and Paleolithic human biology.

[18] What Will the New Cardiovascular Risk Calculator Mean for Patients? (2024) Harvard Medical School: The Predicting Risk of Cardiovascular Disease Events (PREVENT) model could significantly reduce the number of statin-eligible adults.

[19] Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion (2000) The New York Times: Pfizer purchased Lipitor?s manufacturer for $90.2 billion.

[20] Pharmaceutical Mycelia: A story of statins LGC Standards: Early statins derived from Penicillium and Aspergillus inhibit HMG-CoA reductase to lower cholesterol.

[21] A New Women?s Issue: Statins (2014) The New York Times Well Blog: Cardiologists raise concerns over limited evidence for statin benefits in women due to underrepresentation in trials.

[22] Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak (2016) JAMA: Researchers highlight inflated benefits of statins and incomplete adverse event data.

[23] Medical Marketing in the United States, 1997-2016 (2019) JAMA: U.S. medical marketing expenditures rose from $17.7B in 1997 to $29.9B in 2016, with limited regulation of misleading ads.

[24] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part I (2004) Journal of Lipid Research: Nikolai Anitschkow induced vascular lesions in rabbits by feeding them cholesterol, resembling human atherosclerosis.

[25] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (2005) Journal of Lipid Research: Research supported lowering cholesterol through dietary changes; confirmed in the Framingham Heart Study.

[26] Primary nonadherence to statin medications: Survey of patient perspectives (2021) Preventive Medicine Reports: In this study, over half of the patients prescribed statins but not taking them never informed their prescribers, often preferring lifestyle changes or natural remedies.

Epipen is an exquisitely engineered, expertly marketed, totally modern drug. And it?s an amazing success story, especially if you count success through dollars - Epipen sales rose from $200 million in 2007 to $1 billion a year in 2015 to more than $2 billion in 2023. Epipen is what they call in the pharma business, a blockbuster.

The story of Epipen is also a story of unintended consequences and unexpected discoveries, one that goes from the Azores, some islands in the middle of the Atlantic Ocean, to Sweden, the home of the Nobel Prize, to Vietnam, during the Vietnam War.

This story also lands very close to home. Today, Epipens are in schools, they?re in malls, they?re on airplanes, they may even be in your backpack or purse or glove compartment - just in case. So in this episode, we?ll learn all about that.

And there?s also the biggest unintended consequence of all. It turns out that for many of the millions of people like Alex who live with food allergies - and the risk of anaphylaxis - their condition may in fact be the result of one of the biggest blunders of the past century of medicine and public health.

Sources for this episode

[1] A Mighty Pen (2013) Science History Institute Museum and Library: In the 1970s, inventor Sheldon Kaplan developed an epinephrine autoinjector in response to the need for rapid, self-administered injections to treat anaphylactic shock.

[2] Auvi-Q Versus EpiPen: Preferences of Adults, Caregivers, and Children (2013) The Journal of Allergy and Clinical Immunology: This study evaluates preference for the Auvi-Q epinephrine autoinjector over the EpiPen among adults, caregivers, and children.

[3] Epinephrine Administered in Anaphylaxis: The Evolution of 0.3 mg Dosage (2023) Therapeutic Advances in Allergy and Rhinology: Anaphylaxis was first formally discovered by French scientists Charles Richet and Paul Portier in experiments with dogs. They found that dogs became more sensitive, rather than less sensitive, to a toxin after an initial small dose.

[4] Northeastern alumnus the genius behind life-saving EpiPen (2016) Northeastern Global News: Sheldon Kaplan reengineered a Cold War-era device, the ComboPen, that delivered a nerve agent antidote, into a device that delivered epinephrine. The new device, EpiPen, was patented under Kaplan?s name in 1977.

[5] Body and Mind; Backward Protection (1989) New York Magazine: Anaphylaxis is a biological mechanism where the immune system provides misguided ?backwards protection? by overreacting to allergens such as nuts, penicillin, or insect stings.

[6] The Use of Adrenal Substance In the Treatment of Asthma (1900) Journal of the American Medical Association: Early research by Dr. Solomon Solis-Cohen showed that using extracts from animal adrenal glands could significantly relieve asthma symptoms by strengthening blood vessels and reducing swelling in the airways.

[7] The Allergy Epidemics: 1870?2010 (2015) The Journal of Allergy and Clinical Immunology: The rise in allergies over the past 150 years can be attributed to advances in hygiene and lifestyle changes, such as increased sedentary indoor lifestyles.

[8] History of food allergy and where we are today (2024) World Allergy Organization Journal: Once poorly understood, food allergies are now managed through strategies beyond avoidance, including immunotherapy, biologic treatments, and early allergen introduction for prevention.

[9] How Marketing Turned the EpiPen Into a 20 Billion-Dollar Business (2015) Bloomberg Businessweek: Mylan Pharmaceuticals, the manufacturer of EpiPen, ran marketing campaigns emphasizing the dangers of food allergies and lobbied lawmakers to place EpiPens in schools and public venues. As a result, the EpiPen became a $1 billion-per-year product, and its price increased by 400% after Mylan acquired it in 2007.

[10] Epinephrine: a short history (2015) The Lancet Respiratory Medicine: In 1894, the English physician George Oliver and the English physiologist Edward Schafer discovered the physiological effects of adrenal medulla extract. In 1899, American biochemist John Jacob Abel successfully purified the extract?s active ingredient and named it epinephrine. It was then synthesized in ampules by Parke-Davis & Company in 1909.

[11] The ancestry of allergy: Being an account of the original experimental induction of hypersensitivity recognizing the contribution of Paul Portier (1985) The Journal of Allergy and Clinical Immunology: In 1902, Paul Portier and Charles Richet discovered anaphylaxis after observing that a second, weak injection of sea anemone toxin caused fatal hypersensitivity in dogs rather than the expected immunity.

[12] Feed Your Kids Peanuts, Early and Often, New Guidelines Urge (2017) The New York Times: The National Institute of Allergy and Infectious Diseases shifted its approach to child nutrition in 2017 by recommending that parents introduce peanut-based foods to infants as early as four to six months of age.

[13] Portier, Richet, and the discovery of anaphylaxis: A centennial (2002) The Journal of Allergy and Clinical Immunology: Paul Portier and Charles Richet discovered anaphylaxis while investigating the toxins of marine life aboard the yacht of Prince Albert of Monaco in 1901.

[14] The Prevalence of Chronic Respiratory Disease in the Industrial Era The United States, 1895?1910 (2003) National Bureau of Economic Research: Chronic respiratory disease prevalence rose in the United States between 1895 and 1910 due to rapid urbanization, industrial pollution, and the emergence of cigarettes.

[15] Shock Reaction Following Ingestion of Mango (1965) Journal of the American Medical Association: A case study on an anaphylactic-like response to mango helped establish early clinical understanding of food-induced anaphylaxis.

[16] Slow Epinephrine In the Treatment of Chronic Asthma (1939) The Journal of Allergy: This 1938 study shows that mixing epinephrine with peanut oil allows the body to absorb the medicine more slowly than the standard water-based version. By delaying absorption, patients can reduce the frequency of injections.

Diabetes and anxiety and insomnia and depression and food allergies. For every modern malady, there are drugs promising to fix it. SO MANY DRUGS.

But they never really fix the problem, do they? Yes, drugs can help people manage their disease. They treat the symptoms. But they rarely remedy what caused the disease in the first place. And therein lies a story. Launching Jan. 6, 2026.