The Milestones series of books tackles big subjects one page at a time. We've had the pleasure of introducing you to a few of them by Clifford Pickover, The Medical Book, The Math Book, and The Physics Book. Now comes The Drug Book: From Arsenic to Xanax, 250 Milestones in the History of Drugs by Michael C. Gerald. Like others in the series, The Drug Book devotes a page of text and a page of illustration to milestones, this time in medicine, from the gathering of medicinal herbs around 60,000 BCE to the promising uses of gene therapy in the near future. In between you'll learn about how the medicines that keep us going came about. You may be surprised at how old some of them are! Here are a few excerpts from The Drug Book.

1250 Arsenic

Agrippina the Younger (15–59), Rodrigo Borgia (1431–1503), Cesare Borgia (1476–1507), Lucrezia Borgia (1480–1519), James Marsh (1794–1846)

When arsenic comes to mind, few think of its medical uses, which date back to ancient Greece and China more than two millennia ago. More recently, potassium arsenite— now a reputable anticancer treatment—was sold as an early cure-all medication in 1786. Of far greater significance, arsphenamine (Salvarsan), an organic arsenic-containing drug, was the first authentic cure for syphilis, which plagued humankind beginning in the sixteenth century.

The King of Poisons. Arsenic’s role as a medicine, however, is dwarfed by its esteemed reputation as a poison between the times of ancient Rome and the nineteenth century. It was first isolated as an element in 1250. The poison of choice for nefarious professionals, arsenic trioxide (white arsenic) is colorless, nearly tasteless, and readily dissolvable in water and other drinking liquids. Thus, victims are oblivious to their impending doom. While the signs and symptoms of strychnine and cyanide poisoning are obvious, family members, physicians, and authorities might unwittingly attribute arsenic-induced vomiting, diarrhea, and muscle cramps to any number of ailments.

Among the most infamous and highly successful early poisoners was Agrippina the Younger. Sister of Caligula, she used arsenic to dispose of her husband, freeing her to marry the Roman emperor Claudius, her uncle. Many poisonings later, her sixteen-year-old son Nero became emperor. “La Cantarella” arsenictrioxide powder was a family trademark perfected by the Borgias of Renaissance Italy—particularly Rodrigo (Pope Alexander VI) and his children, Cesare and Lucrezia. La Cantarella was said to induce a deep, death-simulating sleep lasting for four hours, during which time the user had no detectable pulse. Juliet may have taken this potion while awaiting Romeo. Two centuries later, Tofana of Sicily’s arsenic solution Aqua Tofana was reportedly responsible for the deaths of 500–600 persons.

The epoch of the “inheritance powder” declined significantly in 1836, when the British chemist James Marsh developed an irrefutable and highly sensitive chemical test for the presence of this poison in tissues.

SEE ALSO Atoxyl (1905), Salvarsan (1910).

1456 Witches' Flying Ointments

Johannes Hartlieb (1410-1468), Alfred J. Clark (1885-1941)

Accounts of the Sabbat or Black Mass, dating from the fifteenth to eighteenth centuries, related stories of nighttime meetings attended by witches, demons, and Satan, in which wild dancing and sexual orgies occurred. Why did the accused women confess that they were consorting with the devil when the penalty for witchcraft was death, either by hanging or burning at the stake? Torture, perfected by the Inquisitors, undoubtedly loosened many guiltless tongues. The use of "flying ointments," first described in 1456 by the Bavarian physician Johannes Hartlieb, may have also played a role in their heartfelt confessions.

Witches were said to fly to the Sabbat on brooms, cats, or other animals. They acquired this "power of flight" by applying a sooty green ointment containing plant extracts, which may have produced physiological changes that simulated the sensation of flight. A number of questions have been raised about the nature of these ointments, including their supposed ingredients and where they were applied.

If, as was generally accepted, they slathered their bodies with the ointment, the active chemicals would have had to cross the formidable barrier of the skin to enter the bloodstream. However, if the ointment were applied to the vaginal area, perhaps with a broomstick as some writers suggest, absorption would have been more certain and perhaps account for the sexual fantasies accompanying the Sabbat.

Flying ointments were many in number and varied in composition. Several such ointments were analyzed by the distinguished University College, London, pharmacologist A. J. Clark, who concluded that, among the multiple ingredients, aconite and belladonna were most worthy of consideration. Clark speculated that the sensation of flying might have arisen from a fluttering, irregular heartbeat caused by the aconite, as well as an excitement progressing to delirium caused by the belladona.

In 1692, nineteen women and men were convicted of witchcraft and executed in Salem, Massachusetts. Executions for witchcraft ended in Europe at the close of the eighteenth century.

SEE ALSO Belladonna (1542), Aconite (1762).

A 1508 woodcut by Hans Baldung depicts Hexen (witches) preparing for the Sabbat.

1797 Absinthe

The Green Fairy of Art and Literature. Switzerland has the dual distinction of being the first country to commercially manufacture absinthe in the 1790s and among the first in Europe and North America to ban it one century later. During the intervening period, the "green fairy" was mythicized in the works and by the drinking habits of artists and writers living in France, including van Gogh, Manet, Toulouse-Lautrec, Picasso, Baudelaire, Hemingway, Rimbaud, and Wilde.

During the early years of the twentieth century, absinthe drinking lost its mystique and was linked to violent crimes and social disorder. This led to bans on its manufacture in much of Europe (excluding the United Kingdom) and the United States. In the 1990s, the hazards of absinthe were reevaluated, and the potent liquor was returned to the shelves worldwide.

Absinthe is a spirit containing 50-75 percent alcohol, anise (imparting its flavor), fennel, and the leaves of wormwood (Artemisia absinthum). The wormwood leaves contain thujone, absinthe's chief behaviorally active constituent, and its characteristic green color is the result of chlorophyll in the herbs. The method used to prepare the drink generally involves pouring ice-cold water over a sugar cube into a glass that contains the spirit.

Purported effects of absinthe on behavior, including increased clarity of thinking and enhanced creativity or hallucinations and madness, have been the subject of continued controversy and debate. In a 2008 report, chemical analysis revealed that, contrary to expectations, the thujone content of early twentieth century "pre-ban" absinthe was about the same as absinthe produced after 1988, when the European Union lifted its ban. Absinthe's behavioral effects could also be attributed to its high alcohol content: Absinthe containing 70 percent alcohol is 140 proof, whereas most gins, vodkas, and whiskeys are only 80-100 proof. Because there are now no legal or industrial standards or definitions as to what constitutes "absinthe," its content varies widely worldwide.

SEE ALSO Alcohol (c. 10,000 BCE).

This 1896 lithograph advertising Absinthe Robette, drawn by the Belgian artist Henri Privat-Livemont (1861- 1936), is considered among the most iconic Art Nouveau images.

1987 Prozac

Prozac and its half-dozen “band of brothers”—selective serotonin reuptake inhibitors (SSRIs)—are the most commonly prescribed class of antidepressants, in spite of questions regarding their effectiveness. However, there is no question that SSRIs cause fewer side effects and are safer when taken in overdose than the tricyclics.

During the 1970s and 1980s, the link between serotonin and depression became more convincing. Interest focused on the SSRIs, drugs that preferentially increase serotonin at mood-influencing sites in the brain. Prozac (fluoxetine), first approved in 1987 and marketed the following year, was later joined by Celexa, Lexapro, Luvox, Paxil, and Zoloft, plus a generous number of generic equivalents.

The approved medical uses of the SSRI differ somewhat around the world but often include anxiety and panic disorders, obsessive-compulsive disorders (think Lady Macbeth), and clinical depression. When used to treat severe depression, they start producing their beneficial effects in two to four weeks, which is comparable to the tricyclics. To reduce the risk of relapse, a common concern, antidepressants are generally taken for at least six months—and, often, for years—after recovery. Some 20– 25 percent of individuals who abruptly stop taking these medications experience SSRI discontinuation (withdrawal) syndrome.

Notwithstanding their marketplace success, the use of SSRIs is embroiled in controversy. Some 30–40 percent of depressed patients receiving placebos improve, which complicates studies attempting to objectively demonstrate the effectiveness of SSRIs. Two critical meta-analyses of multiple studies appearing in 2008 and 2010 concluded that, when compared with placebos for the treatment of mild to moderate depression, SSRIs provided little or no benefit. SSRIs were, however, quite effective for treating severe depression. Regulatory agencies in the United States and United Kingdom have concluded that SSRIs can increase suicidal thoughts in children, adolescents, and young adults up to the age of twenty-four, although suicide attempts have not increased. This risk has not been shown for adults.

When Eli Lilly’s patent for Prozac expired in 2001, they rebranded Prozac as Sarafem—same drug, different color capsule—at a much higher price than generic fluoxetine for “premenstrual dysphoric disorder.”

SEE ALSO Placebos (1955), Tofranil and Elavil (1957), Monoamine Oxidase Inhibitors (1961).

The Professional Humorists’ Club, a cartoon by Rea Irvin (1881–1972), appeared in Life magazine
in 1914. In the club’s sitting room, various men exhibit sad, depressed, aggressive and angry moods. Irvin was the New Yorker's first art editor.

2018 Smart Drugs

Move Over, Einstein and Mozart. If we believe ads appearing on websites or in print, we are but one pill, Power Bar, drink, or dietary supplement away from having a greater attention span or powers of concentration—perhaps even a greater memory, capacity to learn, ability to solve complex problems, and reasoning prowess. These “miraculous” products are variously called smart drugs, cognitive enhancers, and nootropics (from the Greek, “toward the mind”).

Some purported smart drugs are nutrients and herbals available at health food stores. Others have been approved for use for Alzheimer’s disease or Parkinson’s disease but have never been shown to enhance memory. Currently, the most widely used smart drugs are stimulants, such as Ritalin (methylphenidate) and Adderall (amphetamine salts), which treat attention deficit-hyperactivity disorder (ADHD) or Provigil (modafinal), prescribed to counteract narcolepsy.

As many students and rising executives will attest, stimulants do promote alertness, decrease drowsiness, and increase concentration. However, evidence that such drugs enhance the user’s ability to solve complex problems, write great books, compose symphonies, or make more rational long-term decisions is now absent.

In theory, how might the smart drugs of the future help the user achieve such wonders? Perhaps by increasing the supply of or efficiency in utilizing nutrients and oxygen in the brain. Increasing the synthesis, creating mimics, or improving the effectiveness of neurotransmitters, hormones, or other essential brain chemicals required for memory might work. Still others might facilitate the flow of information between nerves or enhance the utilization of memory stores. Some of these drugs may be of benefit in the treatment of Alzheimer’s disease, and perhaps some anti-Alzheimer’s drugs will enhance normal memory.

Assuming such drugs were safe, effective, and available, who could get them, and would their selective availability be good or bad for society at large? Would using smart drugs in school or on the job provide an unfair advantage, or would they be more like tutors that maximize mental abilities? As we learn more about brain function and its chemistry, such drugs appear to be on the not-so-distant horizon.

SEE ALSO Neurotransmitters (1920), Amphetamine (1932), Ritalin (1955), Dietary Supplements (1994).

This spherical fused gyroscope comes close to achieving perfection, differing from a perfect sphere by no more than 40 atoms. Used in NASA’s Gravity Probe B experiment in 2004, it tested and confirmed two key predictions from Einstein’s 1916 general theory of relativity. Einstein, synonymous with genius, is refracted in the background image.

Michael C. Gerald, PhD is Professor Emeritus of Pharmacy at the University of Connecticut and has served as Dean of the school. The Drug Book: From Arsenic to Xanax, 250 Milestones in the History of Drugs by Michael C. Gerald is available now at Amazon and at a bookstore near you.