How Ancient Cure-Alls Paved the Way for Drug Regulation

A king’s quest to protect himself from poison led to an explosion of expensive potions that were prescribed for every ailment—until officials started reining them in.

An apothecary publicly preparing the drug theriac (Wikimedia Commons )

Martin Shkreli has nothing on Mithridates VI. During his reign (120 to 63 B.C.E.), this king of Pontus (located on the southern edge of the Black Sea) worked as a toxicologist in between waging wars on Rome. His efforts to create a universal antidote helped pave the way for modern drug regulation.

Hellenistic monarchs frequently used poison to alter the political landscape around them, whether to kill themselves or rivals. Most famously, Cleopatra VII of Egypt killed herself by snakebite in 30 B.C.E. And Mithridates’s contemporary Ariarathes VI, the king of Cappadocia (south of Pontus), came to the throne after his five elder brothers were poisoned, likely by their own mother.

Mithridates first learned about poisons at a young age. His father, Mithridates V, was poisoned, possibly at his mother’s behest, as Adrienne Mayor, Mithridates VI’s biographer, suggested in her book The Poison King. Afraid he’d be next, the young Mithridates began to study their properties. The Roman natural historian Pliny the Elder called him, “with his brilliant intellect and wide interests … an especially diligent student of medicine, [who] collected detailed knowledge from all his subjects.”

Once he became king, Mithridates consulted physicians, scientists, and shamans in the hopes of creating a foolproof remedy to toxins. He worked with his court botanist, Krateuas, and corresponded with doctors like Zopyrus, the royal physician in Alexandria, Egypt. Mithridates cultivated unique poisons in his laboratories and gardens, and, some historians say, may have even tested them on condemned criminals, in the interest of finding ways to counteract them.

One ancient medical text, On Theriac to Piso—attributed to Galen, the pioneering medical writer and doctor to Roman emperor Marcus Aurelius—stated, “For this Mithridates … wanted to test the effect of pretty much every single simple drug which is used against poisons, trying their effects on criminals condemned to death.”

The most famous of Mithridates’s potions was later named mithridatium. Taken daily as an electuary (a pill made of a paste, using honey as a binding agent), mithridatium combined beneficial pharmaka, or drugs and medicines, with poisons. As Galen put it, “Mithridates mixed all these together and made one drug, hoping to have a defence [sic] against all ills.” According to Pliny: “By his unaided efforts he thought out the plan of drinking poison daily, after first taking remedies, in order that sheer custom might render it harmless.”

This way, Mithridates thought to both improve his health and immunize himself simultaneously.  Surviving recipes of mithridatium list dozens of ingredients, ranging from the expected—like opium and myrrh—to the bizarre, like castoreum, a substance found in beaver testicles.

Mithridates took his concoction daily for decades, even while he was fighting the land-hungry Romans for control over much of Asia Minor. In 63 B.C.E., when the Romans were about to capture him, Mithridates tried to commit suicide by poison. But, according to ancient chroniclers like Appian, the daily dosing worked so well that he didn’t die. Instead, in this version of the story, Mithridates made one of his soldiers, a Gaul named Bituitus, gut him.

After Mithridates’s death, the Romans took up his medical mantle. “Poisoning was already becoming widespread in Rome by the end of the Republic,” Mayor wrote in an email. This made the Romans “very keen to acquire … [this] universal antidote.” They “claimed to possess his original recipe and to improve upon it,” she said.

Andromachus, the personal physician to Emperor Nero, created a version called theriac, adding more opium and some viper flesh, thinking that the bodies of venomous animals must contain antidotes. Of this addition, Galen marveled: “There is nothing for you to wonder at in the fact that the same wild beasts can both kill and heal.” Galen himself considered theriac a remedy for all ailments—not just poison—and popularized it by prescribing it to the emperor.

When it came to medicines, Romans held that more expensive and “exotic” ingredients were higher quality and more effective. (Plus, medicine-makers would earn more money selling a more expensive remedy). “Physicians were well aware of the attraction that such an expensive drug could have on a wealthy clientele,” the pharmacological historian Laurence Totelin wrote in an e-mail. To impress their clients, they competed to introduce as many spices and other rare products in their recipes as possible. “Little by little, one expensive ingredient in a recipe ceased to be sufficient, and more and more expensive ingredients were put together, leading to the creation of expensive antidotes such as mithridatium or theriac,” Totelin added.

Over the next few centuries, recipes for universal antidotes proliferated worldwide.

In the eighth century, theriacs appeared in Islamic medical texts as poison-repellants and cure-alls. While some theriacs survived in European writings, many re-entered Western society as old Greek and Roman texts, preserved by Islamic scholars, were re-introduced into the Mediterranean again. They became popular in medieval Europe to combat the Black Plague, and the invention of the printing press facilitated the spreading of recipes. There was no internationally universal recipe—no rules at all, really, for what could and couldn’t be called a theriac.

Throughout the Renaissance and early industrial eras, major centers of trade from London to Cairo had flourishing antidote industries. Often, the jars the remedies came in were as expensive and ornate as what was inside them. Venice’s 60-ingredient theriac (dubbed “Venetian treacle” by the English) became the most famous, but pharmacies across the world popularized different versions.

Theriac was perennially popular because it was thought to cure every ailment, no longer just poison. For poorer apothecaries, producing cheap versions of expensive remedies was good money. If they couldn’t afford expensive ingredients, they might pass off a cheaper medicine as a high-end one. If theriac and mithridatium didn’t work, people thought, the pharmacists must have been at fault. They must have used poor ingredients or prepared the mixtures incorrectly.

Even in Galen’s time, many people screwed up theriacs. He admitted there was “fraud on the part of the hunters as to the identity of the beasts and inexperience on the part of those preparing the drug by mixing in the other ingredients have often rendered the drug useless… Likewise again, there is, as I have said, a great deal of inexperience about the drugs which go into theriac.”

In order to prevent apothecaries from passing off cheap ingredients as expensive ones and poor-quality theriacs (that didn’t adhere to the “official” recipes put forth by medical authorities), as the real thing, city authorities and unions began to oversee production, forming the foundation of modern drug regulation.

Legal penalties for apothecaries improperly preparing remedies and peddling them to the public began to appear during the Renaissance. In 1397 in Sicily, a key point of cultural exchange between the East and the West, King Martin II appointed his personal physician to head a committee called the Protomedicato to supervise all things medical, from surgery to pharmacology. Thus, through a direct representative, the monarch could oversee the kingdom’s flourishing medical trade and legislate how apothecaries made their medicines. This royal regulation, perhaps inspired by existing physicians’ and apothecaries’ guilds, caught on across Europe, expanding a ruler’s power even further.

In 1540, Henry VIII permitted his Royal College of Physicians to assign four of its members to be official inspectors of London apothecaries’ remedies. These men were the king’s secret medical police, examining ingredients and pharmacological wares. If the products were judged to be “defective, corrupted, and not meet nor convenient to be ministered in any medicines for the health of man's body,” according to the Pharmacy Wares, Drugs, and Stuffs Act, ministers had the right to destroy these items (and an apothecary’s livelihood) as they saw fit. If apothecaries refused to allow inspectors into their shops or homes, they would be fined, as would negligent inspectors. Henry’s daughter Mary I improved upon this law in an Act of 1553 to ensure the inspectors examined wares in full view of the apothecaries and increased the penalty for disobedient apothecaries.

With official eyes on them, apothecaries became subject to laws standardizing how their bestselling remedies, like theriac, were produced. If they used unsanctioned recipes, or continued to make theriac after failing an inspection, there’d be hell to pay. A “black market” for theriac existed alongside the official one; with salesmen hawking their own remedies’ virtues, it was hard for patients to be sure they were consuming legitimate medicine.

To make sure everyone was making medicines properly, doctors began to circulate pharmacopeias—manuals outlining official drug preparation. The first modern formulary for apothecaries came from Florence’s physicians’ guild in 1498; other cities across Europe soon followed suit. In 1618, the official formula for mithridatium was published in The London Pharmacopeia, and its production flourished among many apothecaries.

In 1606, the theriac makers of Montpellier, France, formed their own union and passed laws about preparation. In Venice, each St. Bartholomew’s Day (August 24), apothecaries had to make theriac in public before legal witnesses so they couldn’t skimp or substitute any ingredients. Then the potions would sit for 12 years before they could be used.

But over the centuries, as mithridatium and theriac proliferated, there were some dissenters. In one treatise, the 12th-century Muslim philosopher-doctor Averroes claimed that, while it worked as an antidote, when taken repeatedly, theriac could harm a healthy constitution. The 13th-century friar Nicholas of Poland criticized theriac as a quack remedy; he believed that common remedies were more effective than expensive, occult ones.

As scientific methods and experimentation flourished, so did skepticism about cure-alls. The 17th-century French doctor Guy Patin dismissed such “exotic” remedies in favor of simpler, proven ones that were “neither rare nor expensive.” Such doctors remained in the minority until the 18th century, when the trend of polypharmacy (taking multiple drugs—or drugs with many ingredients—at the same time) began to decline because of a growing recognition of drug interaction. Medicines whose benefits were imbued with superstitions also grew less popular, in favor of those proven scientifically effective.

In 1745, the English doctor William Heberden wrote an influential pamphlet called Antitheriaka. He cast doubt on reliability of mithridatium, citing how its ingredients changed over the millennia as an example of its lack of medical legitimacy. Heberden believed theriac was more harmful than helpful—take, for example, the common ingredient of opium—and his followers influenced apothecaries. A mere 40 years after Heberden published his treatise, in 1788, the London Pharmacopeia omitted mention of mithridatium and theriac. Although they fell out of fashion, the cure-alls were still produced in remote areas into the 20th century. Even as modern medicine advanced, the legacy of these ancient remedies and rituals remained. Theriacs were an extreme example of remedies gone astray, so much so that they inspired regulatory structures that continued to shape the pharmacological field long after cure-alls fell out of favor.