Addictions Case Study: Part 3 - Treatment Plan

(Ksir, 2021)

Ksir, C. C. (2021-05-01). Drugs, Society, and Human Behavior, 18th Edition

Chapter 12

Dietary Supplements and Over-the-Counter Drugs

Dietary Supplements

When does “food” become a “drug”? When we think of typical food items, such as a loaf of bread or an apple, it seems unlikely that we would confuse those with drugs, such as a prescription antibiotic or illicit heroin. Both contain chemicals that interact with the body’s ongoing physiology, in one case to provide nutrients, in the other to alter functioning in some way desired by the user. But a huge class of pills, capsules, liquids, and powders that look like drugs, and that many consumers think of and use in the same way as drugs, is legally classified as food products. This is very important to the consumer because of substantial differences in the way foods and drugs are regulated by the Food and Drug Administration (FDA). This distinction has been at the heart of an ongoing conflict between the FDA and various manufacturers of these “dietary supplements” over health-related claims.

To make the food versus drug issue more concrete, let’s think about Saint John’s wort (Hypericum). The plant is a perennial shrub with yellow flowers and, like many plants, a history of use as a folk remedy. An Internet search will find numerous references to Saint John’s wort as a “natural remedy for depression,” or “nature’s Prozac,” and suggestions that it can improve mood, reduce anxiety, and aid sleep. Many people take tablets or capsules containing Saint John’s wort for these purposes. Food or drug? Sure sounds like a drug, right? But both the manufacturers of these products and the FDA have agreed that these products are not drugs, but foods, even though people take them not when they’re hungry, but when they’re seeking relief from depression, anxiety, or insomnia.

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The Food, Drug and Cosmetic Act under which the FDA operates says a product “intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man” is a drug. So, if the users and sellers of Saint John’s wort intend it to be used to mitigate or treat depression, shouldn’t it be considered a drug? Chapter 3 reported that when this whole process of regulating patent medicines began in 1906, the FDA was concerned about purity of the products and accurate labeling so that consumers would know what they were buying. Later, when issues of the accuracy of health claims arose, the FDA’s primary focus was on the claims made on the label affixed to the product. A bottle of Saint-John’s-wort tablets may look like a drug bottle, and the tablets may say “300 mg” and look like drug tablets, but if it was sold in the United States its label will include terms you don’t expect to see on a drug product, such as “nutrition information” and “serving size,” the kind of information you see on breakfast cereal packages. Also, the label will not claim that the product is good for treating depression or insomnia. If it did, it would legally be a drug and subject to FDA regulation.

Remember also from Chapter 3 that drug manufacturers have to demonstrate to the FDA, before marketing the drug, that the drug is (1) safe when used as intended, and (2) effective for its intended use. Since 1906, the FDA has also been concerned about the purity and safety of food products and ingredients, but not with efficacy. Food products contain some ingredients with known nutritional value, but other ingredients that may enhance flavor or simply provide bulk. Processed foods also contain ingredients that are simply preservatives—included to keep the product from going bad, but having no nutritional value. For many years, people have also taken “dietary supplements,” such as vitamins and minerals, meant to ensure sufficient intake of these important chemicals in case they are insufficient in the diet. Ongoing controversy about how much of each vitamin is needed and how much is too much has led to the establishment of “recommended daily allowances,” which are sometimes adjusted in response to industry pressure to raise them or medical research suggesting a need to limit them. Saint John’s wort and a wide variety of other products are now sold as dietary supplements. Under this category, they need to be pure and they need to be safe, but the manufacturer doesn’t have to show to the FDA or to anyone else that they provide any benefit, either nutritionally or as a treatment for disease.

If the “300 mg” tablet of Saint John’s wort contains some amount of the plant, then it’s accurately labeled. With a drug, we’d expect to know exactly how much of the active ingredient it contains, but with a dietary supplement derived from a plant (an “herbal” supplement), we might not even know what the active ingredient is, let alone how much is in the 300-mg tablet. It’s possible that no amount of Saint John’s wort is really effective (the research evidence on this is mixed; see the following page), and also possible that the amount contained in a given pill is too small in any case. That’s legal because the seller isn’t directly making a health claim, so it doesn’t have to demonstrate effectiveness.

In the early 1990s, the FDA had become concerned about two things. One was claims such as “heart healthy” being put on food products, and the other was the rapidly growing market in dietary supplements, fueled partly by Americans interested in healthful nutrition to prevent disease and partly by the emergence of several aggressive multilevel marketing organizations that recruited individuals to become distributors, offering both “wholesale” prices for their own products and the potential of high profits on sales to their friends and neighbors. In 1993, the FDA took two important actions. One was the approval, after careful study, of seven health claims that food manufacturers could use if their products met certain requirements (e.g., foods high in calcium can say they reduce the risk of osteoporosis, and foods low in sodium can say they reduce the risk of high blood pressure). In doing so, the FDA also made it clear it was not going to allow other unapproved health claims on foods. The second important action in 1993 was the release of the publication “Unsubstantiated Claims and Documented Health Hazards in the Dietary Supplement Marketplace.” This document, as well as specific enforcement actions against products the FDA considered to be violating the existing law, led to a rapid and strong reaction on the part of the nutritional supplement industry. Raising fears among customers that the federal government would soon require them to get a doctor’s prescription before they could purchase nutritional supplements, and using the multilevel marketing networks to generate a widespread grassroots campaign, the dietary supplement industry pressured Congress to limit the FDA’s role. In 1994, both houses of Congress unanimously passed the Dietary Supplement Health and Education Act (DSHEA).

The DSHEA made several important changes. First, it redefined dietary supplements to include a variety of substances such as herbs, amino acids, and concentrates and extracts of herbs. Previously, the FDA had only allowed “essential nutrients,” such as vitamins and minerals that were known to be required in a healthy diet, to be sold as dietary supplements in tablet, capsule, or liquid form. Second, the definition of safety was altered so that the FDA could declare a product to be “adulterated” only if it presents “a significant or unreasonable risk of illness or injury.” Any ingredient being sold at the time the DSHEA was passed was presumed to be okay unless the FDA could demonstrate its risk. Any new ingredient introduced after 1994 would need to be accompanied by some evidence that it would not present a significant or unreasonable risk. Previously, an ingredient was not supposed to be sold until after the FDA reviewed it and allowed it to be included on the “generally recognized as safe” list. Third, while a dietary supplement still cannot claim to be a cure or treatment for a disorder, statements can be made indicating the supplement has a beneficial effect on some structure or function of the body, or on “well-being.” The sellers do not have to prove these claims, as they would for a drug, but they have to provide supporting evidence that the claims are not false or misleading. In other words, if there is some indication that the statement is possibly true, and some that it might not be true, then the information can be included because the evidence does not indicate the statement is clearly false and misleading. Finally, products running such statements must also include the following: “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

The result of this 1994 law was that dietary supplement manufacturers were now free to market a wide variety of products without fear that the FDA would consider them to be drugs, requiring solid premarketing evidence of both safety and effectiveness. The already growing dietary supplement market expanded rapidly from an estimated total of $3.5 billion in 1992 to $11 billion in 1995, and by 2019 it was estimated at $32 billion, greater than the market for over-the-counter (OTC) drugs such as aspirin and cough and cold remedies.1

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Was the DSHEA a boon or a threat to consumers? On one hand, consumers now had available a wider variety of products. However, critics say more regulation is needed. In 1994, the FDA first publicized serious concerns about products containing ephedra (see Chapter 6). Many of these products were used by people seeking to control their weight. Ten years later, in 2004, after the widely publicized death of baseball pitcher Steve Bechler, the FDA declared that products containing ephedra did pose significant and unreasonable risk and therefore were not to be sold. That it took 10 years to accomplish this action and that it was up to the FDA to compile evidence supporting the risks are indicators that the burden of proof might have swung too far away from the sellers and onto the FDA. In 2003, Senate hearings were held on whether the FDA needed more authority or simply needed more resources to implement the authority allowed it under the DSHEA. The answer appeared to be some of each. The FDA has the authority to establish “Good Manufacturing Practices” regulations, requiring food makers to establish procedures to ensure that their products contain what they say they contain, and that they are not “adulterated” with unwanted contaminants. With additional resources, the urging of Congress, and the cooperation of many of the larger supplement manufacturers, the FDA announced its Good Manufacturing Practices rules for dietary supplements in June 2007. Each manufacturer will decide what procedures to follow so that pesticides, fertilizers, and so on do not get mixed in, and that the proper ingredients are included in the appropriate amounts. FDA inspectors will spot check to see that these practices are in place. As with most regulations, it is expected that some of the bigger manufacturers will welcome these rules because they will increase public confidence in their products, whereas other manufacturers will have a difficult time meeting the requirements and may be forced out of the business.

Congress also granted additional authority to the FDA in 2006, to set up an “Adverse Events Reporting” process. The rules for that were finalized at the end of 2007. Among other things, each product label now has to include an address where a consumer can report any adverse events that occur after taking the product. The companies are then supposed to compile these reports and provide the data to the FDA. This will help the FDA to discover types of products that might have significant and unreasonable health risks and should be pulled from the market.

In 2014, two young men (18 and 24 years old) died after consuming dietary supplements containing highly concentrated caffeine. Their families contacted the FDA, which began to investigate and to send warning letters to several companies notifying them that their products were considered to have significant health risks. In 2018, the FDA issued guidelines that effectively ban many of these products from being marketed in the United States. The issue is complicated, as are the guidelines. The FDA estimates that toxic effects, including chest pain and irregular heartbeat, begin to occur at about 1,200 mg (1.2 g) of caffeine, about three times the amount in some large coffee drinks (Chapter 11). The lethal dose for an adult is about 10 to 14 g. So, depending on the concentration and packaging, it might be relatively easy for a consumer to obtain a toxic or even lethal dose. At least one of these companies had been offering packages up to 25 kg (25,000 g) of powdered caffeine, enough for 2,000 lethal doses.

Consumer Reports magazine has published a list of dietary supplement ingredients that it considers to be potentially dangerous to consumers (see Table 12.1). The FDA has taken regulatory action against some of these (shown in the table), but most remain on the market unless or until the FDA can develop clear evidence that they present “a significant or unreasonable risk of illness or injury.”

Source: “15 Ingredients to Always Avoid,” Consumer Reports, September 2016. Available at http://www.consumerreports.org/vitamins-supplements/15-supplement-ingredients-to-always-avoid/.

Following a report from the U.S. Government Accountability Office that proposed greater authority for the FDA to regulate dietary supplements,1 Senator John McCain introduced the “Dietary Supplement Safety Act” in February 2010. The proposed law would have required all manufacturers of dietary supplements to register with the FDA and to provide complete lists of ingredients. It also gave the FDA authority to issue a mandatory recall of any ingredients it found to be unsafe. The dietary supplement industry mounted an immediate campaign against this increased regulation, and a month later Senator McCain withdrew the bill.

Some Psychoactive Dietary Supplements

Saint John’s Wort

Saint John’s wort (botanical name Hypericum perforatum) has been used for centuries and was once known as “the devil’s scourge” because it was supposed to prevent possession by demons. In recent years its psychoactive uses have included the treatment of both anxiety and depression. There is limited evidence on the effectiveness of Saint John’s wort in the treatment of anxiety, but several studies have indicated some usefulness in treating depression. One systematic review of 35 controlled clinical trials with Saint John’s Wort in major depressive disorder found moderate evidence that it was superior to a placebo and about as effective as antidepressants.2

The FDA has raised concerns about Saint John’s wort interacting with various prescription drugs (see Chapter 5), so people using it should notify their physicians.

SAMe

S-adenosyl-L-methionine is a naturally occurring substance found in the body. It is an active form of the amino acid methionine, and it acts as a “methyl donor” in a variety of biochemical pathways. (A methyl group consists of one carbon and three hydrogen atoms.) As long ago as the 1970s, SAMe was tested in Italy for its effectiveness as an antidepressant. Several studies have reported that SAMe is approximately as effective as prescription antidepressant medications, although many of the studies have not been well controlled. Researchers continue to investigate the possibility that, by combining SAMe with approved antidepressants, a more rapid remission of symptoms can be achieved.4

Ginkgo biloba

Extracts from the leaves of the Ginkgo biloba tree have a long history of medical use in China. It is not clear which of the identified ingredients in ginkgo are the active agents, and it is not completely clear how effective it is for a variety of uses for which it has been proposed. The substance does reduce blood clotting, so it has been proposed as a blood thinner, which improves circulation. However, combining ginkgo with aspirin, which also reduces clotting, could be dangerous. The most interesting suggestion is that Ginkgo biloba extract might improve memory in Alzheimer’s patients, due to its presumed ability to increase blood circulation in the brain. Several studies have tested ginkgo in both normal and memory-impaired older adults. Overall, the results have found slight improvements for some people, but not a reliable effect that would be really useful.5

Weight-Control Products

People hoping to lose weight are probably the biggest market for dietary supplements. This story can best be told by reference to Herbalife, still one of the largest marketers of dietary weight-loss products. Founded out of the trunk of a car in 1980, many of the original products contained the herb ma huang (see Chapter 6), which contains ephedra, an amphetamine-like stimulant. Sales of these products exploded, thanks partly to an aggressive multilevel marketing scheme. By the 1990s, the financial resources of this company, combined with the thousands of distributors in its marketing system, provided a major political push behind passage of the 1996 DSHEA. None of Herbalife’s products contain ephedra, which has been banned by the FDA. Their weight-loss products now include a variety of protein drinks, plus several products they say are designed to promote fat-burning or appetite control. At least some of those products rely on large doses of caffeine to produce the stimulant effect formerly obtained from ephedra. However, as with other nutritional supplements, no scientific evidence of effectiveness is required. Herbalife reported $4.9 billion in worldwide sales in 2019.

Herbalife is far from the only company making lots of money selling nutritional supplements to people who want to lose weight. Many of the products also have significant amounts of caffeine in them. Before buying a product based on a list of botanical names, ask yourself these questions: If a pill says it contains green tea, for example, how much powdered green tea can you even fit in the capsule? If it’s an extract of green tea, what are they extracting, and how much of that is in the pill? Is there supposed to be an active ingredient, and if so, is it present in enough quantity to do anything? The makers of these nutritional supplement products typically reveal none of these answers.

Over-the-Counter Drugs

Over-the-counter drugs are classified as drugs and not dietary supplements. These drugs are self-prescribed and self-administered for the relief of symptoms of self-diagnosed illnesses. The FDA estimates that consumers self-treat four times more health problems than doctors treat, often using OTC drugs.

Americans spend over $23 billion a year on OTC products. That’s not as much as we spend on prescription drugs, alcohol, cigarettes, or illicit cocaine, but it’s enough to keep several OTC drug manufacturers locked in fierce competition for those sales. The two biggest markets are for aspirinlike analgesics and for the collection of cough, cold, and flu products. Do we really need all these nonprescription tablets, capsules, liquids, and creams? How much of what we buy is based on advertising hype, and how much is based on sound decisions about our health? How are we as consumers to know the difference? The FDA is trying to help us with these decisions.

FDA Regulation of OTC Products

The 1962 Kefauver-Harris Amendment required that all drugs be evaluated for both safety and efficacy. The FDA was to set up criteria for new drugs entering the market and establish a procedure for reviewing all the OTC drugs already on the market. At first glance this seemed an impossible task, because there were between 250,000 and 300,000 products already being sold (no one knew for sure how many). In addition, each product was likely to change its ingredients without warning. The FDA made the decision not to study individual products but to review each active ingredient. Many competing brands contain the same ingredients, so there are many fewer ingredients than products. The FDA divided OTC products into 26 classes and appointed an advisory panel for each class. Each panel was to look at the active ingredients contained in the products in its class, decide whether evidence indicated each ingredient was safe and effective for its purpose, and determine what claims could be made for that ingredient on the label. Several of the 26 classes of OTC drugs to be reviewed by the FDA included psychoactive ingredients: sedatives and sleep aids, analgesics, cold remedies and antitussives, antihistamines and allergy products, and stimulants.

Before the panel could begin work, some rules had to be laid down about what was meant by such terms as safe and effective, keeping in mind that no drug is entirely safe and that many might have only limited effectiveness. The FDA uses the acronym GRAS (“generally recognized as safe”) to mean that, given the currently available information, people who are informed and qualified would agree that the ingredient should be considered safe. “Safe” means “a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse.”

Similar acronyms are used for two other important concepts: GRAE (“generally recognized as effective”) and GRAHL (“generally recognized as honestly labeled”). “Effective” means that there is “a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed.” The advisory panel was to rule on each active ingredient and decide whether the evidence indicates that the ingredient is both GRAS and GRAE, or failed on one or both criteria, or if further information was needed.

The overall result of this procedure can be seen by taking a trip to your neighborhood drugstore and looking at the lists of ingredients on medications of a given type. All the competing brands contain much the same few ingredients. In some classes, there might be only one approved active ingredient, meaning that all competing brands are essentially identical. The differences among them often are in the long list of other (inactive) ingredients (colorings, flavorings, etc.). The exact number of OTC products on the market is not known because they still come and go and change, but we do know that there are more than 300,000, and they contain fewer than 1,000 total active ingredients now reviewed in over 80 therapeutic classes.

Simplifying Labels

Both the safety and effectiveness of OTC drugs depend greatly on consumers using them according to the directions and warnings on the label. To reduce confusion and make it more likely that consumers will be able to understand the labels, the FDA moved in 1997 to create uniform standards for labels, with minimum print size, topics in a consistent order (active ingredients, directions for use, warnings), and bold, bulleted headings. One important change was to make the language clearer and more concise, avoiding medical terminology (e.g., “pulmonary” replaced by “lung”). This new, consistent approach to labeling has made it easier to compare products and their ingredients.

Over-the-Counter versus Prescription Drugs

The 1938 Food, Drug, and Cosmetic Act established a classification of drugs that would be available only by prescription. A drug is supposed to be permitted for OTC sale unless, because of potential toxicity or for other reasons (e.g., if it must be injected), it may be safely sold and used only under a prescription.

Sometimes the only difference between an OTC product and a prescription product is the greater amount of active ingredient in each prescription dose. More often, however, prescription drugs are chemicals that are unavailable OTC. Until the FDA began its OTC Drug Review process, once a new drug was approved for prescription sale it almost never became available OTC. Neither the FDA nor the manufacturers seemed to have much interest in switching drugs to OTC status. However, the FDA advisory panels that reviewed products in a given OTC category sometimes did more than was required of them. In some cases, they recommended that higher doses be allowed in OTC preparations—and as a result we can now buy higher-strength OTC antihistamines. And in several cases the suggestion was that previous prescription-only ingredients, such as ibuprofen, be sold OTC.

Between 1972 and 1992, 20 ingredients were switched to OTC status. Then the FDA established the Nonprescription Drug Advisory Committee, which has an advisory role regarding all the drug categories and has helped move many more drugs from prescription to OTC. Drugs recently switched to OTC status include the arthritis pain topical gel Voltaren and a Advil Dual action, combining the two analgesics acetaminophen and ibuprofen.6

Behind-the-Counter Drugs?

In 2006, the revised USA PATRIOT Act included a federal requirement that OTC products containing pseudoephedrine be removed from shelves that are accessible to the public and be kept “behind the counter.” This step was taken because pseudoephedrine was being used as a precursor in the illicit manufacture of methamphetamine. Literally hundreds of products in the cough and cold and allergy categories were affected by this new law. Many of the manufacturers reformulated their products to include phenylephrine instead of pseudoephedrine (see Treatment of Cold Symptoms, page 295-296). Others, including Sudafed (obviously named for its main ingredient) made the old formula available behind the counter and also made a reformulated product that could be out on the shelves. Under the current regulations, people who do ask for and purchase the pseudoephedrine-containing products are limited in the quantities they can buy, and they must show identification and sign for the purchase.

Some Psychoactive OTC Products

Stimulants

Stimulants, one of the original FDA categories, is one of the simplest categories. The FDA allows stimulants to be sold to “help restore mental alertness or wakefulness when experiencing fatigue or drowsiness.” If it sounds like caffeine could do this, you’re right! NoDoz, a well-known product that has been around for years, has the tried-and-true formula: 100 mg of caffeine (about the equivalent of an average cup of brewed coffee). The recommended dose is two tablets initially, then one every 3 hours. Another well-known product, Vivarin, contains 200 mg of caffeine, and the initial dose is one tablet. Thus, although the packages look different and different companies make them, a smart consumer would choose between these two based on the price per milligram of caffeine. Or he or she could choose a less expensive store brand, or buy coffee (usually more expensive), or just get enough rest and save money. The labels warn against using these caffeine tablets with coffee, tea, or cola drinks. The only active ingredient the FDA allows in OTC stimulants is caffeine.7

There is a reasonably brisk business in the semilegal field of selling caffeine tablets or capsules resembling prescription stimulants, such as the amphetamines. Many street purchases of speed turn out to contain caffeine as their major ingredient. It is, however, a violation of the controlled substances act to sell something that is represented to be a controlled substance. The FDA has ruled that products labeled as stimulants that contain anything other than caffeine as an active ingredient cannot be sold OTC. The FDA also outlawed OTC products, labeled for any purpose, that contained combinations of caffeine and ephedrine and has taken legal action against several mail-order distributors of such combination products.

Weight-Control Products

The original FDA list of OTC drug categories did not include appetite suppressants or a similar term. Apparently the FDA didn’t think it would be dealing with such a product, because, at the time, the use of the prescription amphetamines for this purpose was under widespread attack. However, data were presented indicating that phenylpropanolamine (PPA) was safe and effective, and by the late 1970s several products were being sold that contained PPA as their only active ingredient. Some studies indicated caffeine could potentiate the appetite-suppressing effect of PPA, and for a brief period during the early 1980s several of the products included both PPA and caffeine. After the 1983 FDA ruling prohibiting such combinations on the grounds that they might not be safe, all products returned to PPA only. The recommended dose for appetite suppression was 75 mg per day. There was some concern about the safety even of 75-mg doses, with the threat being increased blood pressure resulting from sympathetic stimulation. There was also some controversy about the effectiveness of PPA, given that its effect, as with most appetite suppressant drugs, is small and rather short-lived.

In November 2000, the FDA issued a Public Health Advisory on the safety of PPA, based on a new study showing that women taking PPA had an increased risk of hemorrhagic stroke (bleeding into the brain, usually a result of elevated blood pressure). The FDA requested that all drug companies discontinue marketing products containing PPA and that consumers not use any products containing PPA. Manufacturers and retailers responded quickly, and by early 2001 no remaining weight-control products contained PPA. Dexatrim, one of the most widely sold products previously based on PPA, was marketing a “natural” (dietary supplement) version containing various herbal products, including a small amount of ma huang (ephedra). Ephedra was found in several weight-control products until its ban in 2004. The current Dexatrim formula relies on “green tea extract” and is sold as a dietary supplement rather than as an OTC drug. Until 2007, there was no FDA-approved OTC weight-control ingredient available to consumers. Orlistat, which had been a prescription-only medicine called Xenical, was switched to OTC status and is being sold under the brand name Alli. Orlistat does its work in the intestine, inhibiting an enzyme that breaks down dietary fats. Therefore, some of the fat that would have been absorbed is instead retained in the intestine and passed out in the feces. When given in conjunction with a restricted diet, orlistat has been shown to help people lose weight, but once the drug is stopped there is a tendency to gain back some of the lost weight. The major problem with using this drug is that the fats and oils that remain in the bowel can lead to loose, oily stools; frequent, urgent bowel movements that sometimes are hard to control; and flatulence. The manufacturer recommends a low-fat diet to avoid as many of these side effects as possible.

The market for weight-control products has shifted largely from OTC drugs to the less well-regulated dietary supplement category (page 284).

Sedatives and Sleep Aids

A few years ago the shelves contained a number of OTC sedative, or “calmative,” preparations, including Quiet World and Compoz, which contained very small amounts of the acetylcholine receptor blocker scopolamine combined with the antihistamine methapyrilene. At the same time, sleep aids, such as Sleep-Eze and Sominex, contained just a bit more of the same two ingredients. The rationale for the scopolamine, particularly at these low doses, was under FDA investigation, but scopolamine had traditionally been included in many such medications in the past. Some antihistamines do produce a kind of sedated state and might produce drowsiness. The FDA advisory panel accepted methapyrilene but eventually rejected scopolamine. For a while all of these medications contained only methapyrilene. Then in 1979, it was reported that methapyrilene caused cancer in laboratory animals, so it was no longer GRAS. Next came pyrilamine maleate, then doxylamine succinate, and then diphenhydramine, all antihistamines. If you bought the same brand from one year to the next, you would get a different formulation each time. But if you bought several different brands at the same time, you stood a good chance of getting the same formulation in all of them.

The sedative category no longer exists for OTC products. One product, Miles Nervine, which went from being a sedative containing bromide salts to a calmative containing whatever they all contained each year, is now Miles Nervine Nighttime Sleep-Aid, containing 25 mg of diphenhydramine. Nytol is also a nighttime sleep aid containing the same ingredient. Sominex and Sleep-Eze are still around, and both contain diphenhydramine.

As we saw in Chapter 7, insomnia is perceived to be a bigger problem than it actually is for most people, and it is rare that medication is really required. Antihistamines can induce drowsiness, but not very quickly. If you do feel the need to use these to get you to sleep more rapidly, take them at least 20 minutes before retiring. Their sedative effects are potentiated by alcohol, so it is not a good idea to take them after drinking.

Analgesics

People and Pain

Pain is such a little word for such a big experience. Most people have experienced pain of varying intensities, from mild to moderate to severe to excruciating. Two major classes of drugs are used to reduce pain or the awareness of pain, anesthetics and analgesics. Anesthetics (meaning “without sensibility”) have this effect by reducing all types of sensation or by blocking consciousness completely. The local anesthetics used in dentistry and the general anesthetics used in major surgery are examples of this class of agent. The other major class, the analgesics (meaning “without pain”), are compounds that reduce pain selectively without causing a loss of other sensations. The analgesics are divided into two groups. Opioids (see Chapter 13) are one group of analgesics, but this chapter primarily discusses the OTC internal analgesics, such as aspirin, acetaminophen, and ibuprofen.

Although pain itself is a complex psychological phenomenon, there have been attempts to classify different types of pain to develop a rational approach to its treatment. One classification divides pain into two types, depending on its place of origin. Visceral pain, such as intestinal cramps, arises from nonskeletal portions of the body; opioids are effective in reducing pain of this type. Somatic pain, arising from muscle or bone and typified by sprains, headaches, and arthritis, is reduced by salicylates (aspirin) and related products.

Pain is unlike other sensations in many ways, mostly because of nonspecific factors. The experience of pain varies with personality, gender, and time of day and is increased with fatigue, anxiety, fear, boredom, and anticipation of more pain. Because pain is very susceptible to nonspecific factors, studies have shown that about 35 percent of patients will receive satisfactory pain relief from a placebo.

Aspirin

More than 2,400 years ago, the Greeks used extracts of willow and poplar bark in the treatment of pain, gout, and other illnesses. Aristotle commented on some of the clinical effects of similar preparations, and Galen made good use of these formulations. These remedies fell into disrepute, however, when St. Augustine declared that all diseases of Christians were the work of demons and thus a punishment from God. American Indians, unhampered by this attitude, used a tea brewed from willow bark to reduce fever. This remedy was not rediscovered in Europe until about 200 years ago, when an Englishman, the Reverend Edward Stone, prepared an extract of the bark and gave the same dose to 50 patients with varying illnesses and found the results to be “uniformly excellent.” In the 19th century, the active ingredient in these preparations was isolated and identified as salicylic acid. In 1838, salicylic acid was synthesized, and in 1859 procedures were developed that made bulk production feasible. Salicylic acid and sodium salicylate were then used for many ills, especially arthritis.

In the giant Bayer Laboratories in Germany in the 1890s worked a chemist named Hoffmann. His father had a severe case of rheumatoid arthritis, and only salicylic acid seemed to help. The major difficulty then, as today, was that the drug caused great gastric discomfort. So great was the stomach upset and nausea that Hoffmann’s father frequently preferred the pain of the arthritis. Hoffmann studied the salicylates to see if he could find one with the same therapeutic effect as salicylic acid but without the side effects.

In 1898, he synthesized acetylsalicylic acid and tried it on his father, who reported relief from pain without stomach upset. The compound was tested, patented, and released for sale in 1899 as Aspirin. Aspirin was a trademark name derived from the name acetyl and spiralic acid (the old name for salicylic acid).

Aspirin, either in the gastrointestinal tract or in the bloodstream, is converted to salicylic acid. Taken orally, aspirin is a more potent analgesic than salicylic acid, because aspirin irritates the stomach less and is thus absorbed more rapidly.

Aspirin was marketed for physicians and sold as a white powder in individual dosage packets, available only by prescription. It was immediately popular worldwide, and the U.S. market became large enough that it was very soon manufactured in this country. In 1915, the 5-grain (325-mg) white tablet stamped “Bayer” first appeared, and, for the first time, aspirin became a nonprescription item. The Bayer Company was on its way. It had an effective drug that could be sold to the public and was known by one name—Aspirin—and the name was trademarked. Before February 1917, when the patent on Aspirin was to expire, Bayer started an advertising campaign to make it clear that there was only one Aspirin, and its first name was Bayer. Several companies started manufacturing and selling Aspirin as aspirin, and Bayer sued. What happened after this is a long story, but Bayer obviously lost, and aspirin is now a generic name.

Therapeutic Use

Aspirin is truly a magnificent drug. It is also a drug with some serious side effects. Aspirin has three effects that are the primary basis for its clinical use. It is an analgesic that effectively blocks somatic pain in the mild-to-moderate range. Aspirin is also an antipyretic: It reduces fever. Last but not least, aspirin is an anti-inflammatory agent: It reduces the swelling, inflammation, and soreness in an injured area. Its anti-inflammatory action is the basis for its extensive use in treating arthritis. It is difficult to find another drug that has this span of effects coupled with a relatively low toxicity. It does, however, have side effects that pose problems for some people.

Aspirin is readily absorbed from the stomach but even faster from the intestine. Thus, anything that delays movement of the aspirin from the stomach should affect absorption time. The evidence is mixed on whether taking aspirin with a meal, which delays emptying of the stomach, increases the time before onset of action. It should, however, reduce the stomach irritation that sometimes accompanies aspirin use.

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The therapeutic dose for aspirin is generally considered to be in the range of 600 to 1,000 mg. Most reports suggest that 300 mg is usually more effective than a placebo, whereas 600 mg is clearly even more effective. Many studies indicate that increasing the dose above that level does not increase aspirin’s analgesic action, but some research indicates that 1,200 mg of aspirin provides greater relief than 600 mg. The maximum pain relief is experienced about 1 hour after taking aspirin, and the effect lasts for up to 4 hours.

At therapeutic doses, aspirin has analgesic actions that are fairly specific. First, and in marked contrast to narcotic analgesics, aspirin does not affect the impact of the anticipation of pain. It seems probable also that aspirin has its primary effect on the ability to withstand continuing pain. This, no doubt, is the basis for much of the self-medication with aspirin, because moderate, protracted pain is fairly common. Aspirin is especially effective against headache and musculoskeletal aches and pains, less effective for toothache and sore throat, and only slightly better than placebo in visceral pain, as well as in traumatic (acute) pain.

The antipyretic (fever-reducing) action of aspirin does not lower temperature in an individual with normal body temperature. It has this effect only if the person has a fever. The mechanism by which aspirin decreases body temperature is fairly well understood. It acts on the temperature-regulating area of the hypothalamus to increase heat loss through peripheral mechanisms. Heat loss is primarily increased by vasodilation of peripheral blood vessels and by increased perspiration. Heat production is not changed, but heat loss is facilitated so that body temperature can go down.

More aspirin has probably been used for its third major therapeutic use than for either of the other two. The anti-inflammatory action of the salicylates is the major basis for its use after muscle strains and in treating rheumatoid arthritis.

Effects: Adverse and Otherwise

Aspirin increases bleeding time by inhibiting blood platelet aggregation. This is not an insignificant effect. Two or three aspirins can double bleeding time, the time it takes for blood to clot, and the effect can last 4 to 7 days. There’s good and bad in the anticoagulant effect of aspirin. Its use before surgery can help prevent blood clots from appearing in patients at high risk for clot formation. For many surgical patients, however, facilitation of blood clotting is desirable, and the general rule is no aspirin for 7 to 10 days before surgery.

Aspirin will induce gastrointestinal bleeding in about 70 percent of normal subjects. In most cases, this is only about 5 ml per day, but that is five times the normal loss. In some people the blood loss can be great enough to cause anemia. The basis for this effect is not clear but is believed to be a direct eroding by the aspirin tablets of the gastric mucosa. Aspirin can be deadly with severe stomach ulcers. For the rest of us, the rule is clear: Drink lots of water when you take aspirin or, better yet, crush the tablets and drink them in orange juice or other liquid.

The anticoagulant effect of aspirin has a potentially beneficial effect in preventing heart attacks and strokes. Either can be brought on by a blood clot becoming lodged in a narrowed or hardened blood vessel. Several studies demonstrated that patients who are at high risk for these problems can help to prevent both strokes and heart attacks by taking a small dose of aspirin daily.8 Many patients over a certain age are taking low-dose aspirin (88 mg is typical) regularly, even though the available research doesn’t provide clear evidence for any benefit for low-risk patients.

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In the early 1980s, concern increased about the relationship of aspirin use to Reye’s syndrome, a rare disease (fewer than 200 cases per year in the United States). Almost all of the cases occur in people under the age of 20, usually after they have had a viral infection, such as influenza or chicken pox. The children begin vomiting continuously; then they might become disoriented, undergo personality changes, shout, or become lethargic. Some enter comas, and some of those either die or suffer permanent brain damage. The overall mortality rate from Reye’s syndrome is about 25 percent.

No one knows what causes Reye’s, and it isn’t believed to be caused by aspirin. However, data suggest the disease is more likely to occur in children who have been given aspirin during a preceding illness. In late 1984, the results of a Centers for Disease Control and Prevention pilot study were released, indicating that the use of aspirin can increase the risk of Reye’s syndrome as much as 25 times. In 1985, makers of all aspirin products were asked to put warning labels on their packages. These labels recommend that you consult a physician before giving aspirin to children or teenagers with chicken pox or flu.

In early 1986, it was reported that fewer parents in Michigan were giving aspirin to children for colds and influenza, and the incidence of Reye’s syndrome had also decreased in Michigan. The Michigan study lends further strength to the relationship between aspirin use and Reye’s syndrome. No one under the age of 20 should use aspirin in treating chicken pox, influenza, or even what might be suspected to be a common cold.

Aspirin has long been associated with a large number of accidental poisonings of children, as well as with suicide attempts. It has now been joined on the DAWN lists (see Chapter 2) by its relatives acetaminophen and ibuprofen. Together, these drugs received about 100,000 mentions in the most recent DAWN emergency room data.

Mechanism of Action

Prostaglandins are local hormones that are manufactured and released when cell membranes are distorted or damaged—that is, injured. The prostaglandins then act on the endings of the neurons that mediate pain in the injured areas. The prostaglandins sensitize the neurons to mechanical stimulation and to stimulation by two other local hormones, histamine and bradykinin, which are released more slowly from the damaged tissue. Aspirin blocks the synthesis of the prostaglandins by inhibiting two forms of the cyclooxygenase enzyme (COX-1 and COX-2).

The antipyretic action has also been spelled out: A specific prostaglandin acts on the anterior hypothalamus to decrease heat dissipation through the normal procedures of sweating and dilation of peripheral blood vessels. Aspirin blocks the synthesis of this prostaglandin in the anterior hypothalamus, and this is followed by increased heat loss.

Acetaminophen

There are two related analgesic compounds: phenacetin and acetaminophen. Phenacetin was sold for many years in combination with aspirin and caffeine in the “APC” tablets that fought headache pain “three ways.” Phenacetin has been around since 1887 and had long been suspected of causing kidney lesions and dysfunction. In 1964, the FDA required a warning on all products containing phenacetin, which limited their use to 10 days because the phenacetin might damage the kidneys. In 1983, it was removed from the market entirely.

Acetaminophen has been marketed as an OTC analgesic since 1955, but it was the big advertising pushes in the 1970s for two brand-name products, Tylenol and Datril, that brought acetaminophen into the big time. Acetaminophen was advertised as having most of the good points of “that other pain reliever” and many fewer disadvantages. To a degree this is probably true: If only analgesia and fever reduction are desired, acetaminophen might be safer than aspirin as long as dosage limits are carefully observed. Overuse of acetaminophen can cause serious liver disorders. Acetaminophen has now far surpassed aspirin for both drug-related emergency room visits and drug-related deaths, according to the DAWN statistics (see Chapter 2). The FDA doesn’t want to advertise on the package that acetaminophen can be lethal, for fear of attracting suicide attempts. So it requires a warning against overdose and includes the statement “Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms.” This statement reflects the fact that damage to the liver might not be noticed until 24 to 48 hours later, when the symptoms of impaired liver function finally emerge. You should remember that acetaminophen is not necessarily safer than aspirin, especially if the recommended dose is exceeded. As of 2009, the FDA limited the maximum amount contained in a single capsule to 650 mg for OTC products.

Ibuprofen and Other NSAIDs

Since the discovery that aspirin and similar drugs work by inhibiting the two COX enzymes, the drug companies have used that information to design new and sometimes more potent analgesics, which were introduced as prescription products. Ibuprofen, which originally was available only by prescription, is now found in several OTC analgesics. In addition to its analgesic potency, ibuprofen is a potent anti-inflammatory and has received wide use in the treatment of arthritis. The most common side effects of ibuprofen are gastrointestinal: nausea, stomach pain, and cramping. There have been reports of fatal liver damage with overdoses of ibuprofen, so again it is wise not to exceed the recommended dose.

Ibuprofen was the first of several new drugs that are now collectively referred to as “nonsteroidal anti-inflammatory drugs” (NSAIDs). Naproxen is also available OTC.

One product that luckily did not make the switch to OTC was rofecoxib (Vioxx), which was pulled from the market in 2004 after it was clear that it increased the risk of heart attacks.

Table 12.2 lists several OTC analgesics along with the amounts of each ingredient they contain. The FDA has been discussing whether to exclude products that contain both aspirin and acetaminophen. Products containing ibuprofen warn against combining them with aspirin, because that mixture hasn’t been thoroughly studied.

Cold and Allergy Products

The All-Too-Common Cold

There has to be something good about an illness that Charles Dickens could be lyrical about:

I am at this moment

Deaf in the ears,

Hoarse in the throat,

Red in the nose,

Green in the gills,

Damp in the eyes,

Twitchy in the joints,

And fractious in temper

From a most intolerable

And oppressive cold.9

The common cold is caused by viruses: More than a hundred have been identified. But in 40 to 60 percent of individuals with colds, researchers cannot connect the infection to a specific virus. That makes it tough to find a cure. Two groups of viruses are known to be associated with colds—rhinoviruses and coronaviruses. These viruses are clearly distinct from those that cause influenza or COVID 19. Success in developing vaccines against other diseases has not led to finding a vaccine for the common cold. There may be two main reasons for this: people might not develop any lasting degree of immunity to these viruses after being infected, and also these viruses tend to mutate and change over time.

Viruses damage or kill the cells they attack. The rhinoviruses zero in on the upper respiratory tract, at first causing irritation, which can lead to reflex coughing and sneezing. Increased irritation inflames the tissue and is followed by soreness and swelling of the mucous membranes. As a defense against infection, the mucous membranes release considerable fluid, which causes the runny nose and the postnasal drip that irritates the throat.

Although the incubation period for a cold can be a week in some cases, the more common interval between infection and respiratory tract symptoms is 2 to 4 days. Before the onset of respiratory symptoms, the individual might just feel bad and develop joint aches and headaches. When fever does occur, it almost always develops early in the cold.

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Most of us grew up believing that colds are passed by airborne particles jet-propelled usually through unobstructed sneezing. (“Cover your mouth! Cover your face!”) The old folklore—and the scientists—were wrong. You need to know four things so that you can avoid the cold viruses of others—and avoid reinfecting yourself:

Up to 100 times as many viruses are produced and shed from the nasal mucosa as from the throat.

There are few viruses in the saliva of a person with a cold, probably no viruses at all in about half of these individuals.

Dried viruses survive on dry skin and nonporous surfaces—plastic, wood, and so on—for over 3 hours.

Most cold viruses enter the body through the nostrils and eyes.

Usually colds start by the fingers picking up viruses, either from hand-to-hand contact or from surfaces that have been contaminated within the past few hours. The hands are then used to rub the eyes or pick the nose, and the virus has found its new host.10 The moral of the story is clear. To avoid colds, wash your hands frequently, and avoid touching your face. You don’t have to worry about your pets—only humans and some apes are susceptible to colds.

The experimental animal of choice for studying colds has to be the human. In many studies with human volunteers, three types of findings seem to recur. First, not all who are directly exposed to a cold virus develop cold symptoms. In fact, only about 50 percent do. Second, in individuals with already existing antibodies to the virus, there might be only preliminary signs of a developing cold. These signs might last for a brief period (12 to 24 hours) and then disappear. Finally, it doesn’t seem to matter whether people are subjected to “chilling” treatment (e.g., sitting in a draft in a wet bathing suit). Being cold has nothing to do with catching a cold.

Treatment of Cold Symptoms

There’s no practical way to prevent colds and no way to cure the infection once it starts. So why do Americans spend billions each year on cold “remedies”? Apparently, it’s in an effort to reduce those miserable symptoms described by Dickens. Cold symptoms are fairly complex, so most cold remedies have traditionally included several active ingredients, each aimed at a particular type of symptom. In some ways, the FDA’s Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Advisory Review Panel probably had the most difficult job: multiple symptoms, many ingredients for each symptom, and rapid changes in scientific evidence during the time it studied these products. In the preliminary report, issued in 1976, the panel approved less than half of the 119 ingredients it reviewed. Modern cold remedies contain three common types of ingredients: antihistamines, for the temporary relief of runny nose and sneezing; sympathomimetic nasal decongestants, for the temporary relief of swollen membranes in the nasal passages; and analgesic-antipyretics, for the temporary relief of aches and pains and fever reduction. The most common antihistamine to be found in cold remedies is chlorpheniramine maleate; the most common nasal decongestant in cold remedies is now phenylephrine. The analgesic-antipyretic is usually acetaminophen.

Table 12.3 gives recent formulations for five popular OTC cold remedies. Note that two of them also contain the cough suppressant dextromethorphan, which is the most common active ingredient in OTC cough medicines.

It is ironic that the one type of ingredient found in almost every cold remedy before the FDA began its review continues to be under attack. The FDA advisory panel had serious questions about the data supporting the effectiveness of antihistamines in treating colds. Although some studies have since reported that chlorpheniramine maleate is better than placebo at reducing runny noses, prompting the FDA to approve several antihistamines, more recent controlled experiments have not found any benefit. A 1987 symposium of specialists concluded that “antihistamines do not have a place in the management of upper respiratory infection, though they continue to be useful for allergy.” Still more studies have been done that question the effectiveness of antihistamines, and congressional hearings were held in 1992, asking why the FDA still allowed antihistamines in cough and cold remedies. They’re still there.

In 2008, the FDA issued a Public Health Advisory warning parents not to give OTC cough and cold products to children under 2 years of age, because of serious and potentially life-threatening effects that are relatively rare but more likely to occur in these very young children. The same announcement recommended that parents or caregivers also use caution if they choose to give cough and cold products to older children up to the age of 11. The most critical parts of this include a reminder that these products do not cure nor shorten the duration of the cold and a caution to read the labels and follow the dosing directions carefully.

Allergy and Sinus Medications

There are other related products on your pharmacy shelves. In addition to the cough medicines, there are allergy relief pills, which rely mainly on an antihistamine, to slow down the runny nose. Sinus medicines use one of the sympathomimetic nasal decongestants (phenylephrine), often combined with an analgesic, to reduce swollen sinus passages and to treat sinus headache.

Choosing an OTC Product

By now you should be getting the idea that, thanks to the FDA’s decision to review ingredients rather than individual formulations, you as a consumer can now review and choose from among the great variety of products by knowing just a few ingredients and what they are intended to accomplish. Table 12.4 lists only seven ingredients. Those seven are the major active ingredients to be found in different combinations in OTC stimulants; sleep aids; weight-control products; analgesics; and cold, cough, allergy, and sinus medications.

Do you want to treat your cold without buying a combination cold remedy? If you have aches and pains, take your favorite analgesic. For the vast majority of colds, the slight elevation in temperature should probably not be treated, because it is not dangerous and can even help fight the infection. Unless body temperature remains at 103°F or above or reaches 105°F, fever is not considered dangerous. If you have a runny nose, you might or might not get relief from an antihistamine. Generic chlorpheniramine maleate or a store-brand allergy tablet is an inexpensive source. These will probably give you a dry mouth and might produce some sedation or drowsiness (which, of course, is why some of the more sedating antihistamines are used in sleep aids). Do you have a stuffed-up nose? Pseudoephedrine nose drops will shrink swollen membranes for a time. Although oral sympathomimetics will work, nose drops are more effective. You can find these ingredients in sinus and allergy preparations. However, these sympathomimetics should be used cautiously. There is a rapid tolerance to their effects, and, if they are used repeatedly, a rebound stuffiness can develop when they are stopped. Do you have a cough? Dextromethorphan can be obtained in cough medications.

Why not buy all this in one tablet or capsule? That’s a common approach. But why treat symptoms you don’t have? During the course of a cold, a runny nose might occur at one time, congestion at another, and coughing not at all. By using just the ingredients you need, when you need them, you might save money, and you would have the satisfaction of being a connoisseur of colds. Then again, given the state of research on the effectiveness of these “remedies,” why buy them at all? It’s easy for a skeptic to conclude that there’s little or no real value in cold remedies. The experts say to rest and drink fluids. But when they actually have a cold, most people are less inclined to be skeptical and more inclined to be hopeful that something will help.

Summary

· In contrast to FDA-approved OTC drugs, dietary supplements do not have to be proven effective. Also, the burden of proof for safety concerns is on the FDA as opposed to the manufacturer.

· Saint John’s wort and SAMe have been proposed to treat depression, but the effectiveness of either is not clear from the available research.

· A drug can be sold over the counter only if a panel of experts agrees it can be used safely when following the label directions.

· For a given category of OTC drug, most of the various brands all contain the same few ingredients.

· OTC stimulants are based on caffeine.

· OTC sleep aids are based on antihistamines.

· Orlistat (alli) is the only FDA-approved weight-control medicine available to consumers.

· Aspirin has analgesic, antipyretic, and anti-inflammatory actions. Acetaminophen, ibuprofen, and other NSAIDs have related effects.

· Cold remedies usually contain an antihistamine, an analgesic, an antitussive, and a decongestant.

· An informed consumer can understand a large fraction of OTC medicines by knowing only seven ingredients.

Review Questions

1. What is the main difference between OTC drugs and dietary supplements?

2. What do the acronyms GRAS and GRAE stand for?

3. What are the criteria for deciding whether a drug should be sold OTC or by prescription?

4. What is the main ingredient found in OTC stimulants?

5. How safe and effective are OTC weight-control products, according to the FDA?

6. Diphenhydramine is found in what three brand-name sleep aids?

7. What effect of aspirin might be involved in its use to prevent strokes and heart attacks?

8. What are the differences in the therapeutic effects of acetaminophen and ibuprofen?

9. What is the most common route for a cold virus to enter a person’s system?

10. Which cold symptoms are supposed to be relieved by chlorpheniramine maleate and which by phenylephrine?

References

1. Shahbandeh, M. August, 2019, Statista.com.

2. Apaydin, E. A., A. R. Maher, R. Shanman, M. S. Booth, J. N. V. Miles, M. E. Sorbero, and S. Hempel. “A Systematic Review of St. John’s Wort for Major Depressive Disorder.” Systematic Reviews 5 (2016), pp. 1–25.

3. Srivatsav, A., A. Balasubramanian, U. I. Pathak, et al. “Efficacy and Safety of Common Ingredients in Aphrodisiacs Used for Erectile Dysfunction: A Review.” Sexual Medicine Reviews 8 (3) (2020), pp. 431–442.

4. Sharma, A., P. Gerbarg, T. Bottiglieri, L. Massoumi, L. L. Carpenter, H. Lavretsky, P. R. Muskin, R. P. Brown, D. Mischoulon, and as Work Group of the American Psychiatric Association Council on Research. “S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research.” The Journal of Clinical Psychiatry 78 (6) (2017), pp. e656–67.

5. Bartochowski, Z., J. Conway, Y. Wallach, B. Chakkamparambil, S. Alakkassery, and G. T. Grossberg. “Dietary Interventions to Prevent or Delay Alzheimer’s Disease: What the Evidence Shows” [published online ahead of print, July 18, 2020]. Current Nutrition Reports 2020;10.1007/s13668-020-00333-1.

6. Consumer Healthcare Products Association. “Ingredients and Dosages Transferred from Rx to OTC Status by the Food and Drug Administration.” Retrieved from www.chpa-info.org, July 2020.

7. FDA. “OTC Stimulant Drug Products, Final Monograph.” Federal Register, February 29, 1988.

8. Steffel, J., J. W. Eikelboom, S. S. Anand, O. Shestakovska, S. Yusuf, and K. A. A. Fox. “The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared with Aspirin in Patients with Chronic Vascular Disease.” [published correction appears in Circulation 142 (1) (July 7, 2020), p. e23].

9. Dickens, C. The Collected Letters of Charles Dickens. London, Chapman & Hall, 1880.

10. Eccles, R., and O. Weber (Eds.). Common Cold. Basel, Switzerland: Birkhauser-Verlag, 2009.

11. Carbonaro, T. M., M. W. Johnson, and R. R. Griffiths. “Subjective Features of the Psilocybin Experience That May Account for Its Self-Administration by Humans: A Double-Blind Comparison of Psilocybin and Dextromethorphan.” Psychopharmacology (Berl) 237 (8) (2020), pp. 2293–304.

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