INTRODUCTION

"Imagine if you're [at a] truck stop, you take two bottles of that and you're driving down the road — now you're high on opioids.”¹ Researcher Todd Hillhouse.

The commentator above is not referring to a product purchased from a seedy individual at the rear of the parking area, but rather something purchased out in the open, off the shelf of the public retail outlet prominently located within the rest area. Can it possibly be true that the public can purchase a product that mimics opioids at a truck stop or convenience store or online, no questions asked? Not only does the drug allegedly produce a “high,” It’s been associated with increasing reports of serious adverse events and addiction.² Shouldn’t the FDA or DEA have regulations in place to prevent this from occurring?

The drug in question is tianeptine, colloquially referred to as “Gas Station Heroin,” and is only one of several examples of a commodity that poses a danger to the public but falls between the cracks of regulatory oversight.

Pharmacists are accustomed to dispensing prescription drugs that have undergone rigid clinical testing and been approved by the United States (U.S.) Food and Drug Administration (FDA). However, many products face less stringent requirements (e.g., over the counter [OTC] drugs, supplements) and some may receive no approval whatsoever. This activity will compare the regulatory standards for several categories of consumer products with an emphasis on substances that circumvent regulatory review.

DRUG APPROVAL

Generally, a drug will undergo some level of review before it makes it way to the public. However, the rigor of the scrutiny varies greatly depending on the nature of the drug.

As you are no doubt aware, prescription drugs on the market have been reviewed by the FDA which assesses evidence that the drug is safe and effective.³ The FDA's Center for Drug Evaluation and Research (CDER) evaluates evidence submitted by the manufacturer to ensure that drugs, both brand-name and generic, are effective for the target condition and that their health benefits outweigh their known risks.³ This is a structured process and generally requires at least two clinical trials. Approved drugs are also subject to post-market surveillance to ensure that they continue to be safe.³

The FDA also has several accelerated approval mechanisms that expedite the marketing of promising prescription therapies that treat serious or life-threatening conditions and provide therapeutic benefit over available therapies. Many drugs have been approved under these programs and have altered the course of treatment since these pathways were developed in 1992, including antiretroviral drugs used to treat HIV/AIDS and targeted anti-cancer agents.³

During the COVID pandemic, pharmacists became familiar with another modified drug approval mechanism, emergency use authorization (EUA).⁴ If the Secretary of Health and Human Services (HHS) declares a public health emergency, the FDA may authorize the emergency use of unapproved medical products or unapproved uses of approved medical products.

The FDA was granted authority to issue EUAs in 2004 when Congress passed the Project BioShield Act. That Act was intended to facilitate the development, procurement, and use of medical countermeasures against chemical, biological, radiologic, and nuclear terrorism agents.⁵ The Act was passed in response to the events following the terrorism episode on 9/11; although the intent was to protect against acts of terrorism, to date the only EUAs issued have been in response to pandemics. Medical products considered for an EUA undergo FDA review, but the standard used for approval is a lower level of evidence (“reasonable to believe that the product may be effective” rather than “effective”) than needed for full FDA approval.⁴ There also must be no adequate, approved, and available alternative to the candidate product for diagnosing, preventing, or treating the disease or condition.⁴ (“Unavailable” includes insufficient supplies of the existing product to meet the emergency while inadequate includes contraindications for special circumstances or populations, for example children.⁴)

Readers will be spared from a detailed review of the drug approval process, since pharmacists probably heard this numerous times while in school, but it is an important reminder that non-prescription compounds do not undergo the same rigorous pre-market evaluation by the FDA. OTC drugs are also approved by the FDA, but under different criteria. The primary difference is that the approval of prescription drugs requires approval of a specific drug product to treat a specific condition. Conversely, most OTC products must only conform with existing OTC monographs that describe the marketing standards including the active ingredients, labeling, and other general requirements.⁶

OTC monographs set the conditions under which OTC drug products are generally recognized as safe and effective for their intended use. A monograph covers active ingredients, dosages, formulations, and labeling claims; a new OTC product does not need FDA approval if its manufacturer complies with the relevant monograph. This is because the FDA had already evaluated the safety and effectiveness evidence as part of its monograph rulemaking process.⁶ However, the FDA assesses monograph compliance as part of its inspection process.⁷

If it is a new OTC product without an existing monograph, the manufacturer must submit a New Drug Application (NDA) with clinical trial data demonstrating safety and effectiveness.⁷

In addition, the sponsor must provide consumer behavior studies demonstrating that purchasers can use the nonprescription drug product safely and effectively without the supervision of a healthcare provider.⁷ Of course, a prescription drug may also become an OTC drug.⁸

In stark contrast, oversight of supplements is much less rigorous. Dietary supplements are not subject to the Food, Drug, and Cosmetic Act (FDCA Act), but rather are regulated by a different law, the Dietary Supplement Health and Education Act (DSHEA). DSHEA, enacted in 1994, states that “the Federal Government should not take any actions to impose unreasonable regulatory barriers limiting or slowing the flow of safe products and accurate information to consumers.”⁹ A dietary supplement is defined as a vitamin, mineral, amino acid, herb or other botanical, or a dietary substance for use by man to supplement the diet by increasing the total dietary intake.⁹

Unlike drugs, supplements are not subject to pre-market FDA approval.¹⁰ (Hence the disclaimer found on supplement labels [“This statement has not been evaluated by the Food and Drug Administration."]). The manufacturer does not have to provide the FDA with the evidence it relies on to substantiate safety before or after it markets its products. However, if a proposed dietary supplement contains a new dietary ingredient, the manufacturer must submit a notification to the FDA 75 days before introducing it to the market. The notice must include information on the basis of which the firm has concluded that the supplement will reasonably be expected to be safe.¹⁰ (Only a notice is required, the FDA does not evaluate the data.)

Manufacturers and distributors have the initial responsibility for ensuring that their dietary supplements meet the safety standards for dietary supplements. In general, the FDA’s ability to take action is limited to postmarket enforcement.¹¹ Manufacturers and distributors must record, investigate, and forward to FDA any reports they receive of serious adverse events associated with the use of their products.

The FDA cannot conduct post-market research on supplements to corroborate a manufacturer’s claims. It can only issue warning letters asking manufacturers to voluntarily recall adulterated or misbranded products. If a manufacturer refuses to voluntarily recall its product, the burden is on the FDA to prove that the supplement is harmful or adulterated.¹¹ The FDA must show that the dietary supplement has a significant or unreasonable risk of causing injury or illness, a very high bar. In addition to issues of safety, problems exist with respect to the purity and bioavailability of some products.¹¹

Supplement manufacturers do have restrictions on the types of claims they can make. They may not claim to diagnose, mitigate, treat, cure, or prevent a specific disease or class (which would make them a drug, hence the second part of the label disclaimer: “This product is not intended to diagnose, treat, cure, or prevent any disease”) but may claim to aid a structure or function of the human body, benefit a classical nutrient disease, or promote general well-being.¹⁰

PAUSE AND PONDER: Should supplements be subject to more stringent regulations and if so, in what ways?

IF I’M NOT A DRUG NOR A SUPPLEMENT, WHAT AM I?

Despite all these regulatory pathways providing some degree of control, products can wind up being available for retail sale without any oversight. As noted above, an example of this is tianeptine, which is not FDA-approved, is not generally recognized as safe for use in food, and does not meet the statutory definition of a dietary ingredient. It is, nevertheless, commonly available from retail outlets.¹²

“Gas Station” Drugs

A growing number of substances are available from gas stations, convenience stores, bodegas, vape shops, and even the Internet; they may even be purchased by minors.¹³ They have been given the label “gas station” drugs.

It is believed that the first instance of a “gas station” drug was the emergence of “Spice,” a synthetic cannabinoid (producing cannabis-like effects) in 2008.¹³ The drugs were sold under the guise of being herbal incense or potpourri to circumvent the approval process; the FDA eventually placed the drugs in Schedule I in 2011. A similar pattern was seen a few years later with synthetic cathinones being sold as “bath salts” with “warnings” that they were for external use only, even though testimonials clearly indicated that they were being taken internally. (Cathinone is a naturally occurring beta-ketone amphetamine analogue from the leaves of the Catha edulis plant. Synthetic cathinones derivatives may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects.) The Drug Enforcement Administration (DEA) eventually banned them after a series of fatalities occurred.¹³ Typically, substances like these continue to be sold until their dangerous consequences are recognized and there are calls to restrict them.¹³

Some examples of unregulated drugs available today include delta 8/10 tetrahydrocannabinol, Royal Honey, and Rhino which contain sildenafil, tianeptine, kratom, and phenibut.¹³ The latter three substances will be discussed more fully below.

PAUSE AND PONDER: What would you do if someone asked, “Does the pharmacy sell (one of the gas station drugs)”?

Tianeptine

One of the newer emerging gas station threats is the sale of products containing tianeptine.¹⁴ Tianeptine was synthesized in France in 1971 as an analog of the newly discovered tricyclic antidepressants. It was approved in France as an antidepressant in 1989 and is now available in more than 60 countries.^13,15

Tianeptine [(7-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino)heptanoic acid)] is an atypical tricyclic antidepressant approved in some European, Asian, and Latin American countries primarily for the treatment of major depression. It has also been used to treat anxiety and irritable bowel syndrome.¹³ Unlike traditional tricyclics which block serotonin reuptake in the CNS, tianeptine actually increases serotonin uptake.¹³ However, it is now believed that its antidepressant activity is related to modulating glutamate-mediated pathways involved in neuroplasticity (a process that involves adaptive structural and functional changes to the brain; in other words, the brain's ability to absorb information and evolve to manage new challenges).¹⁵ Unlike conventional tricyclic antidepressants, tianeptine is not primarily metabolized by cytochrome P450s, but is largely metabolized by β–oxidation (which would be a consideration with regard to potential drug interactions).¹⁵

More significantly for the purpose of this activity, tianeptine acts as a full agonist at the mu-opiate receptor and a weak agonist at the delta-opioid receptor.^13,14 It is moderately potent but highly efficacious as a mu agonist.¹⁵ As such, it causes opiate-like euphoria and carries a significant risk of overdose.¹³ Moreover, it has a short half-life that can lead to rapid withdrawal, increasing its potential for addiction and misuse.¹³ Some of the countries where tianeptine has been approved to treat depression and anxiety have restricted how tianeptine is prescribed or dispensed, or warned of possible risk of addiction.¹³

In the U.S., tianeptine is not an approved prescription drug, but has become more visible as an OTC product sold in retail stores under the names of ZaZa Red, Tianna Red, Neptune’s Fix, Pegasus, TD Red, and others.¹² The drug has earned the nickname “gas station heroin” due to its opioid-like effects and potential for similar abuse.¹²

U.S. law enforcement has encountered tianeptine in various forms, including bulk powder, counterfeit pills mimicking hydrocodone and oxycodone pharmaceutical products, and individual stamp bags (small wax packets commonly used to distribute heroin).¹⁴ Tianeptine has also been combined with antidepressants and antianxiety medications; patients often combine the drugs themselves, and some manufacturers make fixed-dose combinations.¹⁴

Tianeptine-containing products available to consumers include some with high doses and are making dangerous and unproven claims that tianeptine can improve brain function and treat anxiety, depression, pain, opioid use disorder, and other conditions.¹² Case reports in the medical literature describe U.S. consumers ingesting daily doses on the order of 1.3 to 250 times (50 mg to 10,000 mg) the daily tianeptine dose typically recommended in labeled foreign drug products.¹²

Risks

Reports of adverse reactions and adverse effects involving tianeptine have been increasing in the U.S.¹⁶ Poison control centers have reported that cases involving tianeptine exposure increased nationwide, from 4 cases in 2013 to nearly 350 cases in 2024. From 2020 to 2022, more than 600 calls were made to poison control centers after exposure, and five deaths occurred as a result.¹⁶

The FDA has identified cases in which consumers have experienced serious harmful effects from abusing or misusing tianeptine including agitation, drowsiness, confusion, sweating, rapid heartbeat, high blood pressure, nausea, vomiting, slowed or stopped breathing, coma and death.¹⁶ Naloxone is an appropriate countermeasure in cases of severe poisoning, since tianeptine has opioid effects.¹³ Users frequently consume tianeptine chronically and, if they stop tianeptine abruptly, they may experience withdrawal symptoms similar to those associated with opioid discontinuation (e.g., craving, sweating, “goose flesh,” diarrhea, myalgias).¹⁶ Tolerance and dependence appear to develop quickly.¹⁷ Severe withdrawal symptoms in humans that have led to hospitalization following the use of tianeptine have also been reported.^12,16

Like many drugs of this nature, tianeptine is frequently found combined with other illicit ingredients, often synthetic cannabinoids, which are not included on the product label.¹⁷ Poison control centers describe the signs of overdose to vary widely and include clamminess, nausea, low blood pressure, and unconsciousness as well as seizures and severe stomach cramps.¹⁷

It is difficult to get an accurate picture of the extent of tianeptine abuse. Reports to poison control centers are voluntary and hospitals do not test for it, so its prevalence is likely underreported.¹⁷ The drug also has a strong following on social media where its merits are hotly debated with one social media forum called “Quitting Tianeptine” attracting more than 5,000 followers.¹⁷

Regulation

Clearly, tianeptine is not an FDA-approved medication. Could its sale at convenience outlets be justified as being designated a dietary supplement and therefore an appropriate consumer product covered by DSHEA? The FDA says it does not meet the statutory criteria for a dietary supplement.¹⁸

Therefore, in the FDA’s view, “It is an unsafe food additive, and dietary supplements containing tianeptine are adulterated under the FD&C Act” (i.e., not “legal”). Nevertheless, many tianeptine products, frequently of non-U.S. origin, are openly marketed as supplements with many consumers mistakenly believing that it is a safe alternative to street opioids.¹⁷

FDA Action

In May 2025, the FDA issued warnings to consumers about the “dangerous and growing health trend facing our nation” about the increasing number of adverse events, including death, associated with tianeptine-containing products.¹² The agency warned consumers not to purchase or use any tianeptine product due to serious risks. The agency also issued warning letters to companies distributing and selling tianeptine products and issued an import alert to help block shipments to the U.S.¹⁹ However, its sale is not restricted.

Several states have taken steps to limit sales of these products. Some states have placed tianeptine on controlled drug schedules.²⁰ At least eight states (AL, FL, GA, IN, KY, MN, OH, VA) classify tianeptine as a C-I drug. Five others (AR, MI, NC, OK, TN) have placed it in C-II and Mississippi considers it a C-III substance. Other states have similar restrictions under consideration.²⁰

Increasing the control of tianeptine is also being discussed at the federal level. In 2024, members of Congress wrote to the FDA urging them to take steps beyond the issuing of warnings, stating that they believed that “more action on tianeptine use is needed to ensure the health and well-being of the American people.”²¹ There is a bill pending in Congress that would place the drug in C-III.²²

A more recent Congressional proposal would ban the sale of tianeptine entirely.²³ It remains to be seen if additional regulation becomes a reality.

KRATOM

Tianeptine is not the only product to exist in a regulatory gray area. Another example with a long history of regulatory wrangling is kratom.²⁴ Kratom (Mitragyna speciosa korth) is a tropical tree indigenous to regions of Southeast Asia (Thailand, Malaysia, Myanmar) and belongs to the same family as the coffee tree.²⁵ Traditionally, Thai and Malaysian laborers and farmers chewed the leaves to relieve fatigue. It has also been used as a substitute for opium when opium is unavailable and chronic opioid users have used it to manage opioid withdrawal symptoms.²⁵ Soldiers returning from the Vietnam war and immigrants from Southeast Asia introduced kratom to America.²⁶

The principal constituents of Kratom, mitragynine (MTG) and 7-hydroxymitragynine (7-HMG), have opioid receptor activity.²⁵ These compounds are indole alkaloids structurally related to yohimbine and have shown anti-inflammatory and analgesic activity in experimental animals.²⁷

MTG and 7-HMG both bind to the human opioid receptors with nanomolar affinity; they function as partial agonists at the mu-opioid receptor and weak antagonists at kappa-opioid and delta-opioid receptors.²⁷

7-HMG exhibits approximately 5-fold greater affinity at the mu-opioid receptor compared to MTG. In rats, MTG does not exhibit abuse liability and decreases the reinforcing effects of morphine. On the other hand, 7-HMG demonstrates abuse liability and increased morphine self-administration.²⁷ MTG can be converted to 7-HMG both in vitro and in a mouse model. It is likely that at least some of the activity attributed to kratom may be due to its metabolic conversion to 7-HMG.²⁷ It has been suggested that individuals who self-administer kratom tea to treat pain, addiction, or depression might achieve very different results depending on the alkaloid profile of the product that they use.²⁷ If so, it would be difficult for consumers to predict the magnitude of activity to expect from ingesting the product since the product labeling does not reflect the variability in alkaloid content .²⁷

Kratom produces both stimulant and sedative effects. At low doses, kratom produces stimulant effects, with users reporting increased alertness, physical energy, talkativeness, and sociable behavior, while high doses produce opioid effects including sedation and euphoria.²⁵ Effects occur within five to 10 minutes after ingestion and last for two to five hours.

The most significant issue with products labeled “kratom” is the introduction of high concentrations of a metabolite (7-HMG) as the most abundant alkaloid. The most abundant alkaloid in traditional kratom products is mitragynine, with concentrations ranging from 54% to 66% of the total alkaloid content. Many other alkaloids comprise the remaining 34% to 46% of total alkaloids, but 7-HMG only constitutes less than 1% of the total. In its natural, fresh state, kratom leaves do not contain 7-HMG. “Kratom” products, often enhanced with extra 7-HMG, are available from Internet sites where it is promoted as a legal psychoactive product.²⁵ Website entries include listings of vendors, methods of preparation, user experiences, and alleged medicinal uses.²⁵ Kratom products are commonly sold in powder form, which is bitter, and users typically consume it as a capsule or use the powder to make tea.²⁶ Common uses are as an alternative to prescription opioids for pain, self-management of opioid or other substance use disorder (including easing withdrawal symptoms), or treating anxiety and depression.^25,26 Reports of adverse effects have increased as the drug has become more popular, with more frequent admission to a healthcare facility and serious medical outcomes, such as seizure, respiratory distress, or slow heart rate.²⁶ According to data from the FDA's adverse event reporting system, mitragynine was involved in 1,255 cases from 2008 to September 2024 of which 1,171 cases were classified as serious and 637 cases resulted in death.²⁵

Regulatory Actions

The risks associated with kratom have prompted government officials to try to restrict its sales for almost a decade, but these efforts have been largely unsuccessful. In 2016, the DEA published its intent to temporarily place MTG and 7-HMG into Schedule I.²⁸ (The Controlled Substances Act empowers the Attorney General to temporarily place a substance into Schedule I for two years without regard to other administrative requirements if there is a finding that such action is “necessary to avoid an imminent hazard to the public safety.”) This decision was based, in part, on the DEA’s finding that the “severity of the reported outcomes, health effects, and increased use of kratom suggests an emerging public health threat.”²⁸ Organizations promoting kratom use did not receive this decision favorably.^24,26

Shortly after the DEA published its notice of intent, a “March for Kratom” was organized at the White House and the protests convinced 51 members of Congress on both sides of the aisle to sign a letter disagreeing with the DEA’s decision.²⁶ Kratom supporters also sent a petition containing more than 145,00 signatures opposing the DEA’s decision to President Obama.²⁶

Kratom advocates stressed several points. They disputed the DEA’s claim about the magnitude of the harm that the substance was producing and also cited reports of possible beneficial effects of kratom as a useful alternative to opioids in managing pain and treating opiate addiction. They maintained that kratom is safer than prescription opioids and that the deaths associated with kratom could be due largely to the simultaneous use of other substances.²⁶ Supporters also posted numerous online testimonials from users touting kratom’s beneficial effects.²⁶

As a result of the backlash, the DEA withdrew the proposed action less than two months after the initial publication, citing numerous comments from the public. The DEA initiated a period of public comment on the scheduling recommendation and received over 23,000 comments with 99% of them opposing the ban.²⁶

A year later, the FDA renewed its effort to schedule the kratom alkaloids and submitted an “eight factor” analysis to the DEA (see the SIDEBAR).²⁶ A month later, the FDA announced a public health advisory on kratom and supported stricter regulation by asserting that kratom was associated with 36 deaths and has similar effects and dangers to other opioids. This was followed by a recall based on contamination of samples with Salmonella or heavy metals.²⁶ However, its legal status has remained unchanged.

SIDEBAR: DEA 8 Factor Test

In determining into which schedule a drug or other substance should be placed, or whether a substance should be decontrolled or rescheduled, certain factors are required to be considered by the Controlled Substances Act [21 U.S.C §811(c) ].²⁹ These are

1. Its actual or relative potential for abuse.
2. Scientific evidence of its pharmacological effect, if known.
3. The state of current scientific knowledge regarding the drug or other substance.
4. Its history and current pattern of abuse.
5. The scope, duration, and significance of abuse.
6. What, if any, risk there is to the public health.
7. Its psychic or physiological dependence liability.
8. Whether the substance is an immediate precursor of a substance already controlled under CSA.

In 2021 the World Health Organization (WHO) announced that it would conduct a review of kratom as part of its role in making public health recommendations to the international community. The FDA participated in this process by submitting information, although two U.S. Senators urged the agency to oppose any effort to add kratom to the list of internationally controlled substances.²⁶ Ultimately, the Committee concluded that there is insufficient evidence to recommend a critical review of kratom.³⁰

The controversy over kratom has not abated, however. In 2023, bills were introduced in both houses of Congress to “protect access to kratom.”^26,31 The bills did not expressly address the legal status but would require the HHS Secretary to hold at least one public hearing to discuss the safety of kratom products. Significantly, if enacted, the law would prohibit HHS from imposing requirements on kratom that are more restrictive than those for foods or dietary supplements.^26,31 It would still permit states to impose more restrictive laws.

More recently, in July 2025, the FDA recommended that products with concentrated levels of 7-HMG be classified as C-I substances; the press release does not define concentrated and the warning only refers to "added" 7-HMG.³² This would apply to products containing high levels of 7-HMG in tablets, gummies, drinks, or parenteral, but not plant, products. FDA Commissioner Makary called the move an “effort to prevent another ‘wave of the opioid epidemic’” from blindsiding the country.”³²

Most states permit the sale, possession, and consumption of kratom, although some set limits.²⁶ There are age restrictions on the sale or possession of kratom products in 18 states; seven of the states restrict the distribution kratom to individuals 18 years of age or older while the other 11 states set an age restriction of 21.²⁶ Tennessee had banned kratom completely, but changed its law to permit natural forms of kratom to be used by individuals over the age of 21.³³ Other states have labelling requirements on kratom products.^26,34 For example, South Carolina passed a law in 2025 mandating that labels must provide details on alkaloid content, serving sizes, and include FDA disclaimers and age warnings. Violations incur civil penalties up to $2,000.³⁴

Some states have taken more aggressive steps to limit access to kratom. Michigan became the first state to ban sales of the drug, classifying it as a Schedule II controlled substance in 2018.¹ As of April 2025, 24 states and the District of Columbia regulate kratom products in some manner.²⁶ Seven states (AL, AK, IN, MI, RI, VT, and WI) and the District of Columbia, treat kratom’s psychoactive components as controlled substances.²⁶

Seven states (AL, AR, IN, LA, RI, VT, WI) effectively ban the sale of kratom by classifying both the plant material and the psychoactive alkaloids as a controlled substance.^33,34 Most have defined it as a C-I substance. Louisiana passed its law in August 2025 classifying the active ingredients, kratom products, and the Mitragyna tree as Schedule I controlled substances. Penalties are severe; producing or distributing kratom can lead to fines up to $50,000 and one to five years in prison, while possession incurs fines up to $1,000 or six months in jail for repeat offenses.³⁴

Other states have enacted more consumer-focused kinds of controls.³⁴ For example, Hawaii requires products to be registered with the Department of Health, have third-party lab testing, and comply with federal good manufacturing practices. Products may not exceed 2% 7-HMG, contain harmful substances like synthetic cannabinoids, or be designed to attract children (e.g., cartoon-shaped products).³⁴ Mississippi requires retailers to obtain permits and imposes an excise tax of $2.50 per ounce for kratom leaf and $5.00 per ounce for extracts.³⁴ Four states (AZ, GA, OK, UT) require that labels indicate the alkaloid content of the product.³⁴

PAUSE AND PONDER: Where should the line be drawn between protecting the public and patient autonomy?

PHENIBUT

Phenibut, known colloquially as Phenigamma and Phenygam among others, is another substance that has evaded regulatory control. Phenibut is a derivative of gamma-amino butyric acid (GABA) and acts as a GABA mimetic primarily at GABA-B receptors (like baclofen); it also affects GABA-A receptors but to a lesser extent. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic transmitter.³⁵ Both its desired and adverse effects appear similar to other GABA receptor modulators like benzodiazepines.³⁶

It was originally developed in the former Soviet Union in the 1960s to relieve anxiety and improve cognitive function in military personnel.³⁷ Later it was introduced into clinical medicine as a treatment for anxiety, insomnia, and various psychiatric conditions ranging from post-traumatic stress disorder to alcohol withdrawal. It has also been used to enhance cognition in young adults and to delay dementia in the elderly. Its presence has expanded to other parts of Europe and the U.S. where it is marketed as a putative OTC cognition enhancer.³⁷ The drug is available in different forms including as a powder, “fine crystals,” and capsules and is also found combined with other substances.^37,38

Phenibut produces a number of adverse effects including drowsiness, lethargy, agitation, tachycardia, and confusion.³⁷ In addition, it can lead to the development of tolerance and dependence and withdrawal may manifest as a severe abstinence syndrome that may require medical intervention.³⁷ The abstinence syndrome resembles benzodiazepine withdrawal and patients may experience insomnia, anger, irritability, tremulousness, decreased appetite, and heart palpations.³⁸ Phenibut also has the potential for interactions with related substances such as anxiolytics, antipsychotics, sedatives, opioids, and anticonvulsants.³⁷

During the period from 2009 to 2019, U.S. poison centers received 1,320 calls about phenibut exposures from all 50 states and the District of Columbia.³⁹ The most commonly reported adverse health effects included drowsiness or lethargy, agitation, tachycardia, and confusion. Coma was reported in 6% of cases. In half of the cases, the exposure resulted in moderate effects with no long-term impairment. About 12% of cases reported life-threatening effects or resulting in significant disability, with three deaths.³⁹ Physical dependence, withdrawal, and addiction have also been reported.³⁸

The FDA issued warning letters to companies whose products contained phenibut and were marketed as dietary supplements as far back as 2019. The FDA concluded that phenibut does not meet the statutory definition of a dietary supplement, and the products were therefore misbranded.⁴⁰ Yet, phenibut is still legally available for sale in the U.S., largely through online sources.

Phenibut has become increasingly available in the U.S. (and European) market, often labelled as a dietary supplement with claims such as promoting focus, relaxation, and positive mood; improving memory and concentration; counteracting irritability and restlessness; and increasing libido.³⁷ Studies of consumers have found that it is frequently purchased as a therapeutic substitute for benzodiazepines, and to manage withdrawal due to benzodiazepines, opioids, and alcohol.³⁷ Nevertheless, the FDA does not regard it as a dietary ingredient and considers phenibut-containing supplements declaring themselves as a dietary ingredient misbranded under the FDCA.

The agency sent warning letters to at least three companies that have marketed products containing phenibut labelled as dietary supplements in 2019. Despite the warnings, the quantity of phenibut increased in three of four brands of OTC phenibut supplements tested following the FDA’s action; in some cases, the amounts detected were 450% greater than a typical 250 mg pharmaceutical tablet manufactured in Russia.⁴¹

The warnings were obviously ineffective and phenibut remains readily available in the U.S., largely online.⁴² Several European countries have made phenibut a controlled substance. In the U.S., Alabama made phenibut a Schedule II drug in 2021and additional states are considering legislation to classify it as a controlled substance.⁴²

PEPTIDES

Another means used to circumvent FDA regulations is to sell drugs on-line advertised as “research compounds” or “lab use” although the promotional material and product reviews clearly show they are being used by individuals who are not enrolled in drug trails. These compounds are readily available online, including through Amazon.com.⁴³

There is a high demand for “research” compounds labelled as “peptides” especially among individuals seeking substances for athletic performance enhancement, improved libido, anti-aging effects, or weight loss (pseudo or real GLP-1 drugs).⁴⁴ This includes existing prescription drugs purchased online through clandestine overseas operations or true research compounds. One example is sermorelin, which modulates the release of growth hormone and allegedly increases muscle mass and possibly enhances libido.⁴⁴ The high demand has led to shortages of prescription products, further stimulating illicit sales.⁴⁴

FINAL COMMENTS

While most therapeutic substances are subject to some degree of control by the FDA, some products available in retail stores or on-line receive no regulatory approval. They present a risk to the public. Manufacturers of these substances may try to circumvent regulation by falsely depicting them as dietary supplements, research compounds, or for external use. Consumers may use these to self-manage their medical conditions or for recreational purposes with a risk of developing serious adverse effects or dependence. The FDA has tried to limit the use of these substances by issuing warnings to consumers and warning letters to manufacturers, but these tactics have had limited success. Pharmacists should be prepared to answer questions about these drugs which commonly gain momentum through social media and should point out that there is no oversight over their claims or safety.

Download CE Activity

“No one recognizes the level of stress they’re putting you under. You’re filling a prescription and the phone is ringing, saying, ‘One pharmacy call, two pharmacy calls, three pharmacy calls.’ I would stand there and feel the sweat come up the back of my neck.” - Pharmacist¹

INTRODUCTION

A recent survey found that more than half of United States (U.S.) consumers worry about potential problems with their prescriptions arising from inadequately staffed pharmacies.² Half of consumers worry about receiving the wrong drug, the wrong dose, or the wrong instructions.² Similarly, a 2024 study by the American data analytics, software, and consumer intelligence company J.D. Power found that overall patient satisfaction with pharmacies has declined, especially among chains, with only mail-order pharmacies showing an improvement in patient satisfaction.³ Only 51% of respondents said their pharmacist is trustworthy.³ The most significant problem areas emerging from the study are long wait times, lower levels of customer trust in pharmacists, and difficulty in ordering prescriptions.³ On a more positive note, 97% of American consumers agree that a pharmacist should have responsibility for informing them about the safety and/or effectiveness of their medications.²

It will probably come as no surprise to readers that pharmacists also report dissatisfaction with working conditions, particularly with issues of staffing, patient aggressiveness, and lack of meaningful communication between pharmacy personnel and management.⁴ The most commonly reported root causes for the disgruntlement were inadequate staffing, the use of performance metrics, and workflow design/policies.

Media reports have described pharmacists at chain pharmacies across the U.S. expressing concern that increased demand for prescriptions, vaccines, and other services are occurring without sufficient staff to fulfill those activities, making it nearly impossible for pharmacy staff to do their jobs properly or safely.⁵ A national survey released in 2022 showed that nearly 75% of pharmacist respondents felt they did not have enough time to safely perform clinical duties and patient care. Nearly two-thirds disagreed with the statement that “employer policies facilitate my ability to safely perform patient care/clinical duties.”⁶ The report also found that three-quarters of pharmacists rated their workload as high or extremely high and that job satisfaction was at the lowest point in 20 years.⁶

Has the modern community pharmacy become a danger to the public? This continuing education activity will examine the current sentiment about the pharmacy workplace, and the perceived risk associated with the current working conditions. It will also review legal and policy changes enacted or contemplated by pharmacists, regulatory bodies, and patients to improve the environment.

THE PHARMACY ENVIRONMENT

In 2022, 6.7 billion prescriptions were dispensed in the U.S., a more than 50% increase from the nearly 4 billion prescriptions dispensed in 2009.⁷ Some pharmacists may feel that they filled that many by themselves.

Currently, almost 70% of people in the U.S. between 40 and 79 years old take at least one prescription drug; 20% take five or more.⁸ In addition to prescriptions, between February 2020 and September 2022, pharmacy staffs administered more than 270 million vaccines, including more than half of all COVID-19 vaccines given in the U.S.⁹ Community pharmacy teams alone accounted for approximately 45% of the total, including more than 8 million COVID-19 vaccines for long term care residents. Pharmacy staffs also provide more than 50 million influenza vaccines per year, supply in excess of 42 million COVID tests, and prescribe and dispense many antiviral medications.⁹ Interventions by pharmacy staffs during this period is conservatively estimated to have averted more than 1 million deaths, 8 million hospitalizations, and saved $450 billion in healthcare costs.⁹

While these data, highlighting pharmacists’ value, should engender a deserved sense of pride, as the opening quote illustrates, pharmacists are also are feeling stress over their workload. Pharmacists interviewed by the Chicago Tribune and the New York Times reporting on pharmacy errors related that they felt flabbergasted by pressures at the workplace to work quickly and meet quotas.^10,11 As a result, a chief executive of a state pharmacy association noted that the number of complaints from members related to staffing cuts and worries about patient safety had become “overwhelming.”¹² Similarly, a survey conducted by the California State Board of Pharmacy found that 91% of chain pharmacists indicated that they lacked the staff needed to ensure adequate patient care.¹³ The Kansas Board of Pharmacy found similar results with more than half of pharmacists polled responding that they didn’t feel they could perform their jobs safely.¹³ The biggest reasons cited were a lack of adequate staffing and employer-imposed metrics, such as filling a specific number of prescriptions a day or providing service to patients within a set time.¹³

These added pressures are consistent with a reduction in the number of pharmacies. Chain pharmacies in particular have been reducing staffing levels and closing pharmacies while simultaneously burdening workers with additional duties.¹³ Staff who do not fill prescriptions or answer the phone fast enough or fail to solicit enough vaccinations reportedly may face discipline, reassignment, or termination.¹³ A former pharmacy school Dean likened the current working environment to the equivalent of a fast-food operation where workers feel pressured to race through every order.¹³

PAUSE AND PONDER: How has your job stress changed in the last few years? Have you seen errors in the workplace?

Consumers are also noticing problems or at least expressing a lack of confidence in pharmacists' attention to detail and public safety. Their concerns are not unfounded. A recent systematic review of 62 studies reported a pooled prevalence of dispensing errors across community, hospital, and other pharmacy settings of 1.6%.¹⁴ [It is difficult to accurately determine error rates due to differences in how studies are conducted, the definition of “error,” and other factors. Consequently, error rates vary widely among different studies. However, a generally accepted reasonable estimate of dispensing errors is approximately 1% to 2%.^15-17 This would represent approximately 67 to 134 million errors each year at the current prescription volume!]

Many factors may contribute to the occurrence of medication errors. An error may occur at any stage of therapy, including prescribing, transcribing, identifying the product, counseling, use by the patient, or monitoring. Errors can occur across all practice settings.¹⁷ Errors may result from an act of commission (e.g., dispensing the wrong drug or dose) or omission (e.g., failure to properly counsel a patient).^18,19 According to the Academy of Managed Care Pharmacy, the most common dispensing errors are dispensing an incorrect medication, dosage strength, or dosage form; miscalculating a dose; and failing to identify a drug interaction or contraindication.¹⁸ Medication errors can cause a range of undesirable outcomes including adverse drug events (dangerous and unintended events), hospitalization, and even death.¹⁷

What’s Workload Got to Do with It?

A few lines of evidence suggest that errors may be associated with workload. Numerous studies have described a relationship between prescription volume and errors.^20-22 A survey of pharmacists in Texas in 2001 found that the estimated risk of errors was positively related to the number of prescription orders filled per hour.²⁰

Other studies found that as prescription volume increased beyond 20 to 24 per hour, the number of errors increased significantly.^20-22 An earlier analysis by a prominent researcher also concluded that the rate of pharmacists’ errors increases after they fill more than 24 prescriptions an hour.²³

The potential for errors is no surprise to pharmacists.¹² One pharmacist reportedly wrote an anonymous letter to his State Board of Pharmacy saying, “I am a danger to the public working for (chain pharmacy).”¹²

Not only is the volume of prescriptions filled by a typical pharmacist a concern for its impact on the risk of errors, but the danger is aggravated by some pharmacy chains’ implementation of time guarantees, promising patients that prescriptions will be filled quickly.^1,12 While the guarantee should provide a benefit to the busy consumer, it is also a safety concern, since the haste to fulfill the guarantee may make it more likely that a medication error may occur. As one pharmacist interviewed by the New York Times wrote, “Metrics put unnecessary pressure on pharmacy staff to fill prescriptions as fast as possible, resulting in errors.”¹² One study of 49 community pharmacists, that had a robust response rate of 90.9%, found that the second most frequent source of error was “patient in a hurry.”²⁴

The former Dean quoted above also believes that “at … the huge pharmacies, errors are a cost of doing business.”¹³ One chain store pharmacist told a reporter that she was reprimanded for taking too long to verify prescriptions, even though her extra diligence had caught several serious mistakes.¹³

The major chains have made changes to address the pressures on pharmacists and promote a “better work-life balance” according to one chain spokesperson.¹³ Most now provide half-hour lunch breaks for staff and some have reduced pharmacy hours.¹³ However, pharmacists report that their workloads remain the same and that they are pressured to work through lunch or stay late to finish their tasks.¹³ Moreover, pharmacists report that when their hours were cut, they saw a corresponding decrease in their salary.¹³

PAUSE AND PONDER: What could be done to reduce workplace stress at your pharmacy?

PHARMACY DESERTS

Pharmacists are not the only ones strained when pharmacies close; it also increases the burden on patients who are left without easy access to pharmacies and their medications. This phenomenon, referred to as “pharmacy deserts,” creates disproportionate consequences for certain communities, notably in areas of patients with high levels of social vulnerability.²⁵ Poor access to pharmacies is often associated with lower medication adherence.²⁵

A pharmacy desert may be defined as a low-income urban area with no pharmacy within a mile radius for those with adequate vehicle access or half a mile for those with limited vehicle access. In rural areas, it refers to areas without an available pharmacy within a 10-mile radius for those with access to transportation.²⁶

The number of retail pharmacies in the U.S. declined by almost 4% (from 63,218 to 60,755) between 2018 and 2023.²⁷ The decrease was larger (5.9%) in rural communities. During the five-year period, 184 rural communities lost all of their retail pharmacies (although 195 rural communities gained retail pharmacies). The majority of the pharmacy losses in rural communities were among independent pharmacies.²⁷ Pharmacy closures were also more common in Black and Hispanic/Latino neighborhoods putting a further strain on health care accessibility in these communities.²⁵

EFFORTS TO CHANGE THE WORKPLACE

Recognition that the pharmacy workplace can contribute to staff burnout and risks to the public is growing. This has resulted in different types of reactions among various groups with the goal of improving the work environment.

Action By Pharmacists

Some pharmacists who have been adversely affected by the current working environment have responded. One action that pharmacists have taken is work stoppage with dozens and, at least in one case, hundreds of pharmacy personnel in chain stores calling out of work to protest working conditions.⁵ The pharmacists maintained that the increased focus on vaccinations added to their workload and made it more difficult for them to carry out their other duties and created a potentially unsafe condition. One pharmacist claimed that the chain has “turned into a vaccination clinic first and a pharmacy second” and added that “because immunizations are so profitable, filling prescriptions is almost an afterthought.”⁵ In at least one instance, pharmacist organizers planned to stage a multi-day nationwide walkout, termed “Pharmageddon,” to protest unsafe working conditions.²⁸

PAUSE AND PONDER: Under what conditions would you be supportive of pharmacists striking for better working conditions?

Action By Regulatory Agencies

Governmental and professional organizations that oversee the pharmacy profession have also become concerned with potentially unsafe conditions existing in the nation’s drugstores and have taken steps to change the workplace environment.

If a pharmacy staff member commits an error, a State Board of Pharmacy may take disciplinary action, but the application of the action differs among the states.²⁹ In the typical situation, the Board will learn of the incident when a patient or caregiver files a complaint, which the Board is obligated to investigate.^29,30 Most states do not have specific rules or regulations that specify that errors are actual regulatory violations, and most determinations are made on a case-by-case basis.³⁰

The most common types of punitive action include license suspension, probation, or revocation, and fines.³⁰ In a few states, incarceration is also a possible punitive action.³⁰ The most common bases for dispensing punitive action were to address public safety/health concerns and public complaints. At least two states (Maryland and Massachusetts) appear to take a nonpunitive approach, with a focus on system wide improvements rather than individual responsibility, and with punitive action reserved for pharmacists deemed incompetent.³⁰

A majority of state boards do not require pharmacies to report errors, and most investigations focus on pharmacists, not the conditions in their workplaces.¹² Some boards have instructed pharmacists in public meetings to quit or speak up if they believe conditions are unsafe. However, many pharmacists fear retaliation, knowing they could easily be replaced for doing so.¹²

Pharmacists have also reported that errors are not consistently disclosed, even internally.¹³ These pharmacists claim that small mistakes and those discovered early are routinely hidden or remain unreported especially by pharmacists who have previously made an error.¹³  One California chain pharmacist believes that "for every error that gets found out, there will be an error that never gets caught."¹³ Pharmacists also say that even when they do report potentially fatal errors, no one from their companies investigates how they occurred or makes changes to prevent them from repeating.¹³ Obviously these actions put the pubic at risk.

PAUSE AND PONDER: Should the reporting of pharmacy errors to a regulatory body be mandated?

Many pharmacy organizations have advocated for workplace changes to reduce the number of errors, including the elimination of prescription time guarantees.¹⁶ The American Pharmacists Association approved a resolution in 2018 which “encourages the adoption of patient-centered quality and performance measures that align with safe delivery of patient care services, and opposes the setting and use of operational quotas or time-oriented metrics that negatively impact patient care and safety.”⁴

Similarly, the trade group The National Pharmacists Association, advocated for pharmacist dispensing limits more than 30 years ago as a means to promote safety. They recommended that a pharmacist fill no more than 15 prescriptions an hour.²³

The former Dean says, “I don’t think the boards of pharmacy or the colleges of pharmacy or the professional associations are doing enough to address the issues.”¹³ However, in one recent event, the Nevada Board of Pharmacy fined and suspended the licenses of two pharmacists who mistakenly provided a pregnant woman with misoprostol instead of the fertility treatment she was prescribed.¹³ The Board also fined their chain pharmacy employer $10,000. However, the pharmacy’s lawyer objected to the fine saying they did nothing wrong, saying that “the only allegation” against the employer “is that they had these pharmacists.”¹³

Trends in State Intervention

Traditionally, state pharmacy boards and other regulatory bodies have considered sanctions after errors have occurred but have generally refused to intervene over workload complaints.¹³ They have seen their role as protecting consumer safety, not to intrude on what has been regarded as business decisions such as staffing metrics and workload.¹³ However, this stance has been changing.

As early as 2017, the Chicago City Council approved legislation that would limit pharmacists to filling a maximum of 10 prescriptions per hour and also required a 30-minute meal and two 15-minute bathroom breaks for pharmacists working at least a 7-hour shift.³¹ A pharmacy also would need to schedule at least 10 pharmacy technician hours per 100 prescriptions filled. The proposal came in response to an investigation by the Chicago Tribune which found that 52% of local pharmacies tested failed to warn a member of the investigative team of potentially serious or fatal drug interactions when presented with a pair of prescriptions.³¹

A few years later the state of Illinois went further, passing notable changes to their Pharmacy Practice Act in 2020 after the Tribune's undercover investigation.³¹ The Act prohibits a pharmacy from requiring staff to work more than 12 continuous hours, including breaks, per day. This applies to pharmacists, pharmacy technicians, and student pharmacists. It also requires at least one uninterrupted 30-minute meal break and another 15-minute break for a pharmacist working six or more continuous hours per day.³² The pharmacist may not work more than five continuous hours before being given the opportunity for a meal break and must be given access to a private break room if one is available.³²

The regulation permits the pharmacy to close during the break period but does not require closure. The pharmacist must be available for emergencies if the pharmacy remains open. Technicians and other authorized support staff may continue to perform normal duties while the pharmacist is on break, except for duties that require a pharmacist’s professional judgment. Prescriptions that have received final verification by a pharmacist and do not require counseling may be dispensed during the break period.³² If a mandated break period is not provided, the pharmacy must pay the pharmacist three times the pharmacist's regular hourly rate of pay for each workday with no break.

The Tribune’s investigation also prompted Illinois Senator Richard Durbin to call for nationwide policies to protect consumers, including asking the Centers for Disease Control and Prevention (CDC) to determine the prevalence of the problem and to provide guidance to pharmacy boards. He also asked the CDC to examine how workload, company performance metrics that track prescriptions, and the length of time consumers wait for prescriptions may impact patient safety and pharmacist errors.³³

Many years earlier (2007), North Carolina had passed a law restricting a pharmacist’s workday to no more than 12 continuous hours and required breaks for a shift of six hours or more.³¹

Other states have also considered regulations to reduce pharmacy stress, although many face opposition from employers. Minnesota is also considering a bill to require bathroom and meal breaks after pharmacists complained that they were afraid to drink liquids during a shift because they might not be able to get to the bathroom.³¹ New Hampshire also has enacted a rule permitting a 30-minute break for pharmacists who work more than eight hours. The new rule took more than four years to be implemented due to opposition from the pharmacy industry.³¹

The South Carolina board has discussed how to investigate conditions more thoroughly after a mistake. It also published a statement discouraging quotas and encouraging “employers to value patient safety over operational efficiency and financial targets.”³¹

PAUSE AND PONDER: Do you think that mandated breaks are beneficial in increasing safety in the pharmacy?

California recently instituted workplace regulations that go even further. The “Stop Dangerous Pharmacies Act” enacted in 2024 allows the pharmacist in charge (PIC) to make staffing decisions “to ensure sufficient personnel are present in the pharmacy to prevent fatigue, distraction, or other conditions that may interfere with a pharmacist’s ability to practice competently and safely.”³⁵ The California Board of Pharmacy estimates that pharmacists make 5 million errors in the state per year, prompting the need for workplace changes.³⁶ If the PIC is not available, a pharmacist on duty may adjust staffing according to workload if needed.³⁵ The pharmacist on duty may also close the pharmacy if, in their opinion, staffing at the pharmacy is inadequate to provide patient care in a safe manner.³⁷

In addition, a chain community pharmacy is required to be staffed at all times during normal business hours (defined as 8:00 am to 7:00 pm) with at least one clerk or pharmacy technician fully dedicated to performing pharmacy-related services.³⁵ This requirement is waived if the pharmacy’s average daily prescription volume is less than 75 prescriptions per day. However, the exemption does not apply if the pharmacist is also expected to provide additional pharmacy services such as immunizations or tests.³⁵ The new regulations also expanded duties that can be performed by a technician including accepting prescription transfers and clarifications of prescriptions.³⁵

California also prohibits chain pharmacies from establishing a quota related to the duties for which a pharmacist or pharmacy technician license is required.³⁸ (A quota is defined as “a fixed number or formula related to the duties for which a pharmacist or pharmacy technician license is required, against which the chain community pharmacy or its agent measures or evaluates the number of times either an individual pharmacist or pharmacy technician performs tasks or provides services while on duty” and includes prescriptions filled and “services rendered” to patients.³⁸)

However, California and other states have found that enforcing these rules is challenging.¹³ The California State Board of Pharmacy, for example, is coping with routine violations by retail pharmacies that then fail to provide records to inspectors seeking to verify complaints.¹³

Oklahoma also recently established rules to ensure adequate staffing levels.³⁹ Pharmacists are expected to complete a form whenever they are concerned about inadequate staffing due to inadequate number of support personnel or excessive workload. Each pharmacy must review completed staffing reports and address any issues listed and document any corrective action taken or justification for inaction. The reports must be made available to the Board during inspections. There is also a prohibition against disciplinary action or retaliation against the pharmacist filing the report.³⁹

Virginia also passed temporary emergency regulations banning production quotas and increasing staffing in late 2024.¹³ Other states, including West Virginia, New York, and Illinois have attempted to pass legislation similar to California’s prohibition of the use of quotas for duties performed by pharmacists or technicians, but the legislation failed to pass.³⁶

The Ohio Board of Pharmacy also took steps to address the pharmacy staffing shortage with new rules in 2024.⁴⁰ One new rule requires pharmacies to “ensure sufficient personnel are scheduled to work at all times in order to minimize fatigue, distraction, or other conditions which interfere with a pharmacist’s ability to practice with reasonable competence and safety.” It also calls for staffing levels to be based on “other requirements” related to the practice of pharmacy and not solely based on prescription volume and also bans the use of “quotas” for “ancillary services.” (Quotas are defined as “a fixed number or formula related to the duties of pharmacy personnel, against which the pharmacy or its agent measures or evaluates the number of times either an individual performs tasks or provides services while on duty.^”40)

To alleviate burnout that can lead to mistakes filling prescriptions, Ohio’s new rules will require that all pharmacies give all employees working six hours or more an uninterrupted 30-minute break.⁴⁰ The pharmacy does not need to close during the break if the pharmacist remains on the premises and prescriptions may still be sold but the recipient must be provided with an offer to counsel. A person who wishes to speak with a pharmacist must be told that the pharmacist is on break and that they may wait to speak with the pharmacist or provide a telephone number for contact after the break.

Significantly, the new rules require pharmacies to develop a formal system so pharmacists can request additional staff. They also require pharmacy owners to act promptly on those requests and prohibit owners from retaliating against pharmacists who request extra help. A written response to the request must occur within 14 business days and a copy of the response must be maintained in the pharmacy for three years for inspection by the Board.⁴⁰

Ohio’s Board also reacted to patients reporting delays in receiving their medication.⁴¹ The new rules require new prescriptions to be filled within three business days and those subject to auto refill to be done within five.⁴⁰ (The rule has exemptions for shortages, delays in insurance coverage, and where the prescription requires clarification or raises suspicion about its safety or validity.⁴⁰)

Pharmacy chains opposed the new rules.¹³ One chain wrote that the “Board should stay focused on the regulation of the practice of pharmacy rather than the business of pharmacy.”¹³ Chain representatives acknowledged the challenges their pharmacists have faced but denied allegations of unsafe working conditions. They claimed that metrics based on measurable objectives such as quick prescription turnarounds, short telephone hold times, and vaccination volumes are standard within the industry and meant to assess quality rather than penalize staff.¹³

Another effort to reduce errors being considered by some states is mandatory error reporting.³⁷ Pennsylvania requires healthcare facilities to report all incidents of harm and may be the only state currently doing so.³⁷ In Canada, Nova Scotia became the first jurisdiction to implement a requirement for community pharmacies to anonymously report medication incidents to a national repository in 2010 and several other Canadian provinces have followed.⁴² The stated purpose of the repository is to improve medication safety in the community through evidence-informed recommendations for reducing preventable harm related to medications.⁴²

Another approach to reduce errors in the pharmacy is to free up the pharmacist from certain traditional tasks by placing greater reliance on technicians. A formalized program is termed tech-check-tech (TCT) and enables a trained pharmacy technician to perform the final verification on a prescription for which the pharmacist has previously performed the prospective drug utilization review.⁴³ The TCT concept dates back to at least 1978 and has been well validated in institutional pharmacy settings.⁴⁴ Studies have found that technicians perform at least as well as pharmacists in final verification activities in institutional settings and have demonstrated that utilization of technicians in this way allows pharmacists to devote one to five more hours per day to direct patient services.^43,44 While this expanded role for technicians is becoming common in institutional settings, few states have adopted it for use in the community pharmacy.⁴³

PAUSE AND PONDER: In your workplace, what additional tasks could certified technicians perform?

SUMMARY

To err is human, and pharmacy staff will make errors despite their best efforts. Errors can occur at any step during prescription processing. The error rate is not well validated due to many methodological variables, and estimates vary widely although 1% to 2% is a commonly accepted value. However, even at these low rates, the number of patients affected is large and the consequences, although usually minor, can be catastrophic. Pharmacy staffs, of course, do not want to commit errors and removing the triggers for errors is a worthy goal. Evidence supports the concept that workplace pressures and insufficient staffing, high prescription volume, and interruptions and distractions exacerbate the risk of errors. The trend towards reducing the number of pharmacies while expanding pharmacy services has added additional strains to the health care system. Patients have become more aware of the risks associated with the pharmacy environment and burnout. This has also lessened the public’s perception of pharmacists.

Concerns over errors have spurred a growing number of states to revise their Pharmacy Practice Acts to relieve some of the workload pressure on pharmacists. Typical changes include limits on the length of the workday, mandated breaks, limits on the number of prescriptions a pharmacist can dispense over time, and reconsideration of tracking metrics. However, these changes have encountered resistance by employers and implementation and enforcement are spotty. Other changes include expanding the use of technicians and allowing more time for pharmacists to provide services related to patient care. It remains to be seen whether more regulatory oversight of the workplace will impact the number of errors committed. In the meantime, pharmacists and technicians should be extra vigilant to avoid being the object of the next media investigation that casts the profession in a bad light and hope they do not become “a danger to the public.”

Download CE Activity

INTRODUCTION

Kratom. What a funny little word. It's six letters and preponderance of consonants give it an explosive, almost exotic sound. When Pete, a 31-year-old construction worker who has been on workers compensation for six months for a back injury asks about it, the pharmacist, Cindy, is baffled. Educated to never respond with “I don’t know,” Cindy replies, “I don’t know but I will gather some information. Can you give me a couple of days to do some research?” Pete agrees and Cindy gathers information using open-ended questions to determine his goals. Pete says he heard that kratom relieves pain much like opioids do, and it’s a “natural product.” He says that his physician is weaning him from opioids, but he still has pain unrelieved by nonopioid pain killers. His bowling league teammate said “7” would be “better than that regular kratom stuff.” He sees both products at the gas station, and he would like to know if they have the same side effects as opioids do. He says, “I would really like to be done with the constipation.”

PAUSE AND PONDER: What things should Cindy think about as she assesses Pete’s situation?

People native to Southeast Asia (Cambodia, Indonesia, Malaysia, Myanmar, Papua New Guinea, and Thailand) have a deep-rooted history of using kratom, derived from the whole fresh or dried leaves of tropical Mitragyna speciosa trees, dating back centuries.^{1, 2} Once harvested, the leaves can be chewed or brewed into a tea for multiple purposes. Western medical literatures’ earliest mention of kratom dates to the 19^th Century. Traditional uses of kratom in Southeast Asia include improving productivity and combatting physical fatigue in manual laborers, treating morphine dependence, and enhancing religious ceremonies.³

In recent years, kratom-containing products have garnered popularity within the recreational drug market. Approximately five million Americans (aged 12 years old or older) have used kratom.⁴ The predominant demographic of users has recently shifted from middle-aged males to younger people and females.⁵ Consumers can purchase these products in smoke shops, convenience stores, gas stations, and over the Internet without a prescription.⁴ In the United States (U.S.), kratom is available in several dosage forms (capsules, concentrated extracts, powder, raw leaves, and tablets) and doses (depends on the dosage form). Around the world, traditional kratom products have been used as a replacement for traditional opioids or other substances of abuse, or for treatment of anxiety or depression. However, no clinical trials substantiate these benefits.^6,7,8

Cindy focuses on the allegation that kratom and similar products are “natural,” recalling that “natural” is not equivalent to “harmless.” Natural products are often contaminated with elemental impurities (also known as heavy metals).⁹ Kratom specifically can be tainted with heavy metals like arsenic, lead, manganese, and nickel. The Food and Drug Administration (FDA) specifies the permissible daily exposure (maximum acceptable intake) for arsenic, lead, and nickel in dietary supplement products and the tolerable upper intake level of manganese would also be exceeded by some products. However, some kratom products have been found to exceed these regulatory thresholds; non-extract products (capsules, powders, and tablets) often have higher concentrations compared to extracts.⁵

A potential cause of lead and nickel contamination is the country of origin of the kratom trees (Indonesia and Thailand, for example, naturally have greater lead concentrations in their soil and water).^10,11 Local water is used to wash the picked leaves which may leave an elemental impurity residue and the trees themselves can pick up the heavy metal from the soil. Machinery use (harvesting, grinding, storing, and shipping), pesticide and herbicide use, and volcanic rock leeching are the ultimate sources of the heavy metals.^10,11 Regardless of the source, elemental impurities may be retained on harvested, dried leaves which can then be sold to consumers leading to excessive heavy metal exposure. Some products sold as kratom in the U.S. have been adulterated with synthetic compounds such as 7-hydroxymitragynine ((7-OH-MG), an alkaloid of kratom and a growing concern nationally) or even with fentanyl or hydrocodone.¹²

Readers should take a moment to review the various chemical names and pronunciations used in this continuing education (CE) activity in the SIDEBAR.

SIDEBAR: Chemical Components of Kratom

• Alkaloids: natural organic compounds that provide varying physiological effects on animals
• Corynantheidine*: a minor alkaloid of kratom with antinociceptive activity
• Corynoxine/corynoxine B: a minor alkaloid of kratom and derivative of corynantheidine; full agonist of the μ-opioid receptor
• Mitragynine*: a major (most abundant) alkaloid of kratom; provides pain-relieving and stimulating effects
• Mitragynine pseudoindoxyl: a 7-OH-MG metabolite; a more potent μ-opioid receptor agonist compared to mitragynine
• Paynantheine: a major, secondary alkaloid of kratom with high binding affinity to serotonin receptors (5-HT_1A and 5-HT_2B)
• Speciofoline: a minor alkaloid of kratom with no measurable binding affinity at the µ-, δ- or ƙ-opioid receptors
• Speciogynine: a minor alkaloid of kratom with high binding affinity to serotonin receptors (5-HT_1A and 5-HT_2B)
• Specioliatine*: a minor, rare alkaloid of kratom; modulates the pain-relieving and stimulating effects of mitragynine
• 7-hydroxymitragynine (7-OH-MG): an active metabolite of mitragynine; a potent partial μ-opioid receptor agonist exhibiting pain-relief, sedation, and opioid-induced addiction potential (as indicated in animal studies; see below)

*partial agonist of the μ-opioid receptor

Kratom remains a Drug Enforcement Administration (DEA) substance of concern but is not currently scheduled.⁶ Kratom products’ overall risk profile is much lower than some substances of abuse (traditional opioids, amphetamines, cocaine) and similar or slightly lower than cannabis and alcohol.⁷ However, when traditional kratom products are used to treat substance use disorders (SUDs), two observational studies (N = 160, N = 32, respectively) found fewer subsequent episodes of illicit substance abuse and fewer risky lifestyle behaviors such as injecting drugs and needle sharing.^9,13

Another observational study (N = 163) found a lower likelihood of constipation, cravings, fatigue, insomnia, and sexual performance issues than those associated with traditional opioid use.¹⁴ One small clinical trial (N = 26) demonstrated that traditional kratom products can increase pain tolerance. Following a cold pressor task (a procedure where participants immerse their dominant hand into an ice bath and verbally report pain onset), kratom reduced pain sensitivity. The study also suggests that chronic use may cause hyperalgesia (an increased sensitivity to pain) when kratom alkaloid concentrations are low compared to drug-naïve states.^6,15 Whole leaf kratom has modest stimulant effects, so the risk of respiratory depression is low but it does produce adverse events, especially in higher doses, and it has the potential to cause a kratom use disorder (kratom-specific substance use disorder, K-SUD).^6,16  The main adverse events include nausea and vomiting, constipation, tachycardia, hypertension, agitation, confusion, elevated liver function tests, and seizures.

Notable changes have occurred in the kratom product marketplace. In January 2024, an exposition (trade show) in Las Vegas for buyers and sellers of legal recreational substances hosted just two companies selling products with high concentrations of a metabolite (7-OH-MG) as the most abundant alkaloid.¹⁷ By the time the next exposition was held in Chicago in June 2024, 37 companies in the marketplace with 7-OH-MG as a prominent ingredient in a product or products attended; it’s likely that there are many more that did not attend.¹⁷ According to the National Drug Early Warning System (surveillance system that detects early signals of potential drug epidemics), chatter about 7-OH-MG had increased steeply. It rose from roughly 10 posts weekly between September 2023 to November 2024 and spiked to about 20 posts for several weeks from November 2023 to March 2024. From March to June 2024, posts spiked considerably to 30 to 45 posts weekly for several weeks.¹⁸ This CE activity will attempt to tackle several key questions regarding this trend towards higher 7-OH-MG products including

1. How does the alkaloid composition in traditional kratom products compare with high 7-OH-MG concentration products?
2. What do preclinical studies (studies conducted in animal models) suggest about the pharmacologic effects of traditional kratom products compared to high 7-OH-MG concentration products?
3. What insight can be gleaned from consumers about the comparative effects of taking traditional kratom products rather than high 7-OH-MG products?

TRADITIONAL KRATOM VS. 7-HYDROXYMITRAGYNINE

As displayed in Figure 1, the most abundant alkaloid in traditional kratom products is mitragynine, with concentrations ranging from 54% to 66% of the total alkaloid content.¹ Many other alkaloids comprise the remaining 34% to 46% of total alkaloids, but 7-OH-MG only constitutes less than 1% of the total.

Figure 1. Histogram of the Relative Percentage of Alkaloids in Traditional Kratom Products Versus 7-Hydroxymitragynine Products

READING THIS HISTOGRAM: Whole leaf kratom (either fresh or leaf) has 54% mitragynine, 16% specioliatine, 12% cornoxine/cornoxine B, 10% paynantheine, and <1% 7-hydroxymitragynine. 7-OH-MG products contain 93% 7-hydroxymitragynine, 7% mitragynine, and none of these other natural alkaloids.

In its natural, fresh state, kratom leaves do not contain 7-OH-MG; however, 7-OH-MG is a degradation product found minutely in older leaves.¹ In one laboratory evaluation of 53 commercial kratom products, mitragynine, and 7-OH-MG concentrations were related to the speciofoline concentration, a major alkaloid found in the kratom plant that has unspecified activity at the mu and kappa opioid receptors.¹⁹ “High speciofoline” varieties comprised 4.13 mg/G of kratom powder with mitragynine and 7-OH-MG content of 8.13 mg/G and 0.03 mg/G, respectively. “Low speciofoline” varieties had undetectable speciofoline content but mitragynine and 7-OH-MG content of 11.45 mg/G and 0.06 mg/G, respectively. While not found in kratom leaves, the active metabolite of 7-OH-MG is an alkaloid called mitragynine pseudoindoxyl.¹⁹

Although several brands of kratom are available, a popular product is called 7-OHMZ. In this product’s certificate of analysis (CoA; see SIDEBAR), the manufacturer reports 14.9 mg of 7-OH-MG and 1.3 mg of mitragynine per tablet (92% 7-OH-MG).²⁰ A different product, Hydroxie, is an ultra-pure 7-hydroxy kratom. Its CoA shows it contains 16.5 mg of 7-OH-MG and 1.3 mg of mitragynine (93% 7-OH-MG).²¹ A third product, Press’d, has an available CoA that indicates it contains 18.5 mg of 7-OH-MG and 1.5 mg of mitragynine (93% 7-OH-MG).²² The 7-OHMZ and Hydroxie companies state they extract the 7-OH-MG naturally for their products. However, high speciofoline dried kratom leaves contain only 0.03 mg/G of 7-OH-MG. To make a single 7-OH-MG dose with traditional kratom powder, 7-OHMZ and Hydroxie requires between 466 g to 550 g of dried kratom leaves and Press’d requires 616 g of dried leaves which is an entire tree’s harvest of leaves.¹⁹

SIDEBAR: TECH TALK: Understanding Product Verification Absent FDA Approval²³

As kratom and 7-OH-MG products become more available, consumers need to be aware that they are not FDA-approved. Without FDA approval, the FDA takes no responsibility for ensuring that the kratom or 7-OH-MG concentration on the label matches the product content. Monitoring these products is especially important.

Plants can absorb heavy metals, pesticides, and other potentially harmful chemicals that may be in the soil or water easily, and analysts find these contaminants in the leaves, flowers, and stems. Therefore, consumers—and the pharmacists and technicians who advise them—need to investigate the kratom products available on the market if they make recommendations or find a product is widely used in their localities.

Consumers can request products’ Certificate of Analysis (CoA), which provides information about testing for contaminants and active ingredient levels. If the retailer cannot provide it, consumers should avoid that product. States and retailers are starting to take the initiative to ensure consumers have needed information.

When looking at the CoA, consumers can be more confident of the quality if the CoA states that the lab meets “ISO 17025” standards. Consumers can also look to see if the CoA states that the lab complied with the standards set by one of three organizations:

• the Association of Official Agricultural Chemists (AOAC),
• the American Herbal Pharmacopoeia (AHP), or
• the U.S. Pharmacopeia (USP).

Consumers should beware of products that list the total concentration in the product (i.e., 250 mg in the bottle) and not the active ingredient concentration (i.e., 2.5 mg/mL). Of course, products should clearly define a “dose,” and list the amount of active ingredient in a dose and not in the entire product. These products may contain other related compounds besides mitragynine and 7-OH-MG. Consumers should also beware of “proprietary blends” where the alkaloids in the product are given with a total dosage but the amount of each alkaloid is not provided.

PHARMACOLOGIC COMPARISON OF ALKALOID PHARMACOLOGY

Results of In Vitro Studies

Stimulating the μ-opioid receptor with traditional opioids (like morphine) has been associated with feelings of wellbeing, euphoria, pain relief/antinociception (reduced sensitivity to pain), and constipation. It can also lead to central nervous system depression that impairs the normal respiratory response to rising carbon dioxide levels in the blood. Mitragynine and 7-OH-MG are partial μ-opioid agonists while morphine is a full agonist.¹ In an in vitro study, the μ-opioid receptor Ki receptor binding affinity (lower Ki means tighter binding) and EC50 for cAMP accumulation (lower cAMP accumulation means greater suppression of adenylate cyclase production) were determined for mitragynine and 7-OH-MG. The μ-opioid receptor Ki for mitragynine was 15-fold higher than 7-OH-MG (238 nM vs. 16 nM) and 159 times higher than morphine (238 nM vs. 1.5 nM). The μ-opioid receptor cAMP EC50 was 29-fold (398 nM vs. 13.6) higher for mitragynine versus 7-OH-MG and 83-fold (398 nM vs. 4.8 nM) higher than morphine.¹⁹ In other words, 7-OH-MG and morphine bind tighter to the μ-opioid receptor and suppress adenylate cyclase production at magnitudes far greater than mitragynine. For reasons that are poorly understood, mitragynine and 7-OH-MG are less likely to cause respiratory depression than traditional opioids in preclinical studies.^6,19 Other kratom alkaloids (specioliatine, paynantheine, and speciogynine) bind weakly to μ-opioid receptors with Ki values ranging from 410 to 728 nM.¹⁹

Understanding how these products work and their effects on various systems is emerging. The composition of kratom is highly variable; although mitragynine is the predominant alkaloid, around one-third of kratom is composed of other, minor alkaloids. Whether minor or major, kratom’s alkaloids have specific binding affinities and therapeutic outcomes. Physiologic effects of kratom therefore depend on all the alkaloids present. For example,

• Stimulating alpha-1 and alpha-2 adrenoceptors with mitragynine provides modest antinociception (pain reduction). These effects can be attenuated by alpha-1 and alpha-2 antagonists (prazosin—an antihypertensive—and yohimbine—a supplement allegedly used for benign prostatic hyperplasia and sexual function, respectively).¹⁹
• Stimulating alpha-2 adrenoceptors, like with clonidine, can prevent sympathetic outflow (signaling leading to activation of the sympathetic nervous system) in people with withdrawal symptoms from traditional opioids. Research indicates this effect may attenuate opioid withdrawal symptoms that patents experience.
• Mitragynine has moderate nonselective agonist effects across alpha-1 and alpha-2 adrenoceptors with Ki values ranging from 1.3 to 9.3 mcM.
• Speciogynine provides strong alpha-2 agonist effects for many alpha-2 adrenoceptors (Ki for alpha-2A, alpha-2B, and alpha-2C from 0.4 to 2.6 mcM) but has no effect on alpha-1 adrenoceptors.
• Corynantheidine is a potent agonist for alpha-1D adrenoceptors with a Ki value of 0.042 mcM. Stimulation of serotonin receptors can enhance mood and alertness.
• Mitragynine has modest agonist effects at serotonin receptors with Ki values at 5-HT-1A, -2A, and -2B ranging from 1.3 to 5.9 mcM.
• Paynantheine and speciogynine are potent agonists at serotonin receptors with Ki values for 5-HT-1A and -2B ranging from 0.02 to 0.04 mcM and 5-HT-2B Ki values ranging from 0.8 to 1.3 mcM.¹⁹

Traditional kratom products’ pharmacology is complex. Consider this: the human enzyme CYP3A4 converts a portion of mitragynine to 7-OH-MG in the brush border of the gastrointestinal tract and the liver. Next, CYP3A4 circulating in the plasma converts a portion of this active metabolite to mitragynine pseudoindoxyl, a molecule with the ability to interact with central opioid receptors.²⁴ Mitragynine pseudoindoxyl is at least as potent an opioid agonist as 7-OH-MG and lacks alpha adrenoceptor or serotonin receptor effects.²⁵

Human studies are needed to explore kratom's utility in analgesia, euphoria, and addiction more thoroughly. As of January 10, 2025, only nine ongoing studies were listed in clinicaltrials.gov. Most were small, although a few larger studies are underway.^26,27 In one now complete study, human plasma converted 7-OH-MG into mitragynine pseudoindoxyl much more effectively than plasma from other species.²⁵ The percentages of mitragynine pseudoindoxyl formed at the end of 120 minutes of incubation with 7-OH-MG in dog, monkey, mouse, and rat plasma were below 4.3% but 53.8% in human plasma. This suggests that mitragynine pseudoindoxyl’s contribution to the overall opioid receptor’s impact could differ between species. The impact is that pharmacologic effects might also differ between animals and humans with more dangerous effects in people.²⁵ Taken together, the receptor pharmacology of traditional kratom products is a constellation of μ-opioid, alpha-1 and alpha-2 adrenergic, and serotonin receptor effects from multiple alkaloids while 7-OH-MG products focus almost exclusively on μ-opioid receptor effects, which is similar to traditional opioids.^1,6,19,24,25

PAUSE AND PONDER: What takeaways can you list for the heavy science presented in the last few paragraphs?

As Cindy assembles all of the information, she is somewhat confused. She calls a professor at her alma mater and asks if he can discuss these findings with her. After an hour of discussion, she says, “Let me summarize what I have learned so I can explain this to my patient:

• Kratom alkaloids in the highest abundance in whole leaf products primarily interact with alpha-1 and alpha-2 adrenergic and serotonin receptors with indirect and weak opioid effects
• Metabolism of mitragynine via CYP3A4 results in metabolites (7-OH-MG and then mitragynine pseudoindoxyl) that more potently exhibit opioid agonist properties
• 7-OH-MG binds the μ-opioid receptor far greater than mitragynine and 7-OH-MG products have far more 7-OH-MG than whole leaf products could ever provide
• Differences in metabolite amounts and μ-opioid receptor quantities and locations may be species-specific but the effects seen with 7-OH-MG in animals would likely be greater in humans.”

Cindy’s professor says that she got it! He suggests that now that she knows the basic pharmacology, she should move on to some animal studies.

Results of Animal Studies

A step up from in vitro study is the use of animal models. Researchers select animal models carefully based on the purpose of their study. In the case of kratom and 7-OH-MG products, researchers’ intent is to determine how the products compare to opioids in terms of pain relief, euphoria, and addiction potential. For that purpose, the ideal models are small rodents (rats and mice). Many rodent models of pain and addiction exist. Many of the experimental animals can and will self-medicate in response to pain or craving.

A mouse model (tail-flick test) study sought to establish the equipotent antinociception doses of mitragynine and 7-OH-MG.¹ Overall, mitragynine 140 mg/kg subcutaneously provided a similar tail-flick response to 0.7 mg/kg of 7-OH-MG. (See how much more potent 7-OH-MG is compared to mitragynine?) The brain concentrations of 7-OH-MG were almost identical in the mitragynine group (with 7-OH-MG created via metabolism) and the group given 7-OH-MG, suggesting that 7-OH-MG is a driver of mitragynine’s opioid mediated pain-relieving effects.¹ In another mouse study, 7-OH-MG produced a potent antinociceptive effect, similar to morphine and mainly through activation of μ-opioid receptors.²⁸ Tolerance to 7-OH-MG’s antinociceptive effect developed, similar to the tolerance that develops with morphine. Importantly, cross-tolerance to morphine was evident in mice rendered tolerant to 7-OH-MG or morphine when the drugs were switched. Finally, naloxone-induced withdrawal signs occurred equally in mice chronically treated with 7-OH-MG or morphine.²⁸

Overall, 7-OH-MG appears to have greater abuse potential than mitragynine.²⁹ In a rat model, investigators took morphine-addicted rats and allowed them to self-administer 7-OH-MG or mitragynine in a substitution phase. Rats preferred 7-OH-MG over mitragynine and did so in a manner that was dose-dependent and similar to their previous morphine use. After the substitution phase, the researchers allowed morphine self-administration again. Rats using 7-OH-MG ingested higher morphine doses than they had previously while those who used mitragynine ingested lower morphine doses. Nalxonaxine, an experimental μ-opioid receptor antagonist, reduced 7-OH-MG and morphine self-administration doses.²⁹

Less is known about mitragynine pseudoindoxyl’s antinociceptive and withdrawal effects.³⁰ In one model, researchers tested mice to see how long they could retain their tails in a hot water bath at baseline. Then they administered repeated saline or escalating doses of morphine, kratom alkaloid extract, mitragynine, or mitragynine pseudoindoxyl for four days. Immediately before day 5 dosing, the mice previously treated with morphine (~11 + 2 to 2 + 1 s), kratom extract (~10 + 1 to 4 + 1 s) or mitragynine (10 + 1 to 4 + 1 s) demonstrated significantly more drug-induced hyperalgesia, but the normal saline group did not (~10 + 1 to 8 + 1 s). The mitragynine pseudoindoxyl group had reductions from baseline (~11 + 2 to ~6 + 1 s) but this did not achieve statistical significance. Mice were then administered naloxone on day 5 after their assigned drug was administered. When exposed to naloxone, all active groups had less severe withdrawal symptoms than the morphine group for some measures, although for some measures the withdrawal symptoms were greater with the kratom extract, mitragynine, and mitragynine pseudoindoxyl groups than the normal saline group.³⁰

These studies suggest that 7-OH-MG has more potent antinociceptive effects, opioid users would be more likely to seek it, and would promote the subsequent use of higher doses of traditional opioids (called a reinforcing effect) than mitragynine.^28,29,30

In a recent editorial, prominent kratom basic scientists expressed grave concern about 7-OH-MG products.³¹ They believe that manufacturers are taking mitragynine extract and chemically converting it into 7-OH-MG producing unknown alkaloids in the process. Creating alkaloids that do not exist in nature or as a known metabolite in the human body poses unknown risks to patients. They also believe that the pharmacology of 7-OH-MG is inherently riskier than that of mitragynine.³¹

PAUSE AND PONDER: What is the pharmacist’s role in preventing kratom misuse? How would you advise your patients to approach using this product safely?

Kratom this. Kratom that. Cindy is learning all about kratom extracts! After reviewing the animal studies, she calls her professor back. Concerned with the opioid-like properties of kratom’s alkaloids and metabolites, Cindy is unclear if kratom would be a good alternative for Pete’s pain. Cindy’s professor, understanding her concern, sends her to search the World Wide Web for personal, raw experiences from users.

ANECDOTAL EFFECTS OF 7-HYDROXYMITRAGYNINE PRODUCTS

Anecdotal experiences with kratom include discussions of pain relief, energizing or relaxing effects, or its use to prevent opioid withdrawal in between opioid doses, or as a chronic replacement for opioids.^6,8,9,13,14 The euphoric effects caused by traditional opioids reportedly do not occur for many consumers who take traditional kratom products; this makes traditional kratom products an unsuitable substitute for people who use them recreationally.⁸ There is said to be a ceiling effect for the mood elevation with traditional kratom products and that nausea experienced when escalating doses tempers the desire to binge dose.^6,32

The reported consumer experiences with 7-OH-MG products to date are characteristically different than experiences users describe with traditional kratom products.³² Table 1 provides some direct quotes from Reddit chat rooms concerning 7-OH-MG. They are categorized into initial experiences, addiction and withdrawal, and the use of kratom to manage 7-OH-MG withdrawal.³² To summarize these comments, users described 7-OH-MG products’ euphoric effects as more intense. Although the users didn’t report if the pain was due to injury or to hyperalgesia. They reported pain relief but indicated that effects were short lived. 7-OH-MG products can lead to rapid dose increases, with tolerance and withdrawal developing more quickly than with traditional kratom products. A 7-OH-MG addiction can result in financial distress as consumers lose the ability to control their use. A three-tablet pack of Press’d 7-OH-MG 18 mg costs $17 and the suggested dose is ½ tablet. If patients take ½ tablet twice a day, that is $5.70 per day or $2,081 per year. Extrapolating to recreational use and tolerance, patients who take 12 tablets a day expend $68 a day or $24,820 a year. Confusing 7-OH-MG products with traditional kratom products can lead to relapse for consumers using kratom as a chronic opioid substitute.

Table 1. Anecdotal customer experiences with 7-hydroxymitragynine products.³²

Experiencing the euphoric high with 7-OH-MG products (that whole leaf kratom or mitragynine extract products lack) can undo addiction control. Finally, while some consumers try to stop using 7-OH-MG cold turkey, many consumers describe needing to move from 7-OH-MG to whole leaf kratom products or mitragynine extracts to deal with withdrawal symptoms and cravings. Importantly, the posts do not describe people moving from 7-OH-MG to traditional opioids or other illicit opioid-like products such as tianeptine (atypical tricyclic antidepressant with opioid receptor agonist properties; also called “gas station heroin”)(see SIDEBAR). These products were virtually unheard of only a few months ago. It is still too early to know the full measure of adverse events that they could cause.³²

SIDEBAR: TIANEPTINE^33,34

Globally, several health regulatory agencies have approved tianeptine for the treatment of major depressive disorder since its discovery in the 1980s, but the FDA has not. This molecule, originally called an atypical tricyclic antidepressant, appears to have potential benefits for patients experiencing anxiety and irritable bowel disease, but it does not work like other tricyclics. Later research found it targets the opioid mu receptor. Despite its status as an unapproved drug in the U.S., individuals are able to procure it online and at some retail locations (e.g., bodegas, corner stores, gas stations, mini marts, smoke shops). The origins of these substances is sketchy; it’s possible that they are commercially produced by drug manufacturers but just as likely synthesized in underground laboratories. Tianeptine, labeled as "Zaza" and "Tianna Red," has joined the various gas station drugs and has earned the name “gas station heroin.” It is often packaged in shot-sized bottles, and frequently contains synthetic cannabinoids. Recreational users seek tianeptine for its ability to produce a euphoric, opioid-like high. Sadly, chronic use can lead to dependence, tolerance, addiction, and overdose. Some users have attempted suicide. Calls to poison control centers have skyrocketed since 2014.

WHERE SHOULD WE GO FROM HERE?

Why are these products available for sale legally in the U.S.? As noted, several members of Congress asked the DEA not to list kratom products in Schedule I. Traditional whole leaf kratom products contain a natural ingredient with a blend of alkaloids from dried leaves that have effects on opioid receptors (without reinforcing effects), alpha adrenoceptors, and serotonin receptors.⁸ Traditional kratom products have been used around the globe for medical purposes for decades and evidence about its relative safety compared to other substances of abuse is increasing.^6-9,13,14

Congress's concerns included the fact that a bipartisan majority felt that that ban would be made with no opportunity for public comment from researchers, consumers, and other stakeholders. They indicated that such a precipitous decision could be deleterious to consumer access and choice of an internationally recognized herbal supplement; it could also stop progress on studies targeting the treatment of individuals suffering from opioid and other addictions.³⁵

As Cindy did more research, she found that kratom and related products are illegal in some states even though the federal government has not restricted its use. Restrictions may simply impose age limits, employ a more comprehensive kratom consumer protection restrictions, or may ban these products entirely. The Global Kratom Coalition maintains a map (https://globalkratomcoalition.org/regulation-map)³⁶ with updated information of the restrictions in the U.S. (see reference), but it is always wise to determine the laws in your state from original sources. As of January 1, 2025, many states, including California, Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, and Pennsylvania have no statewide restrictions. Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin have outlawed kratom products. Many other states, including Florida, Georgia, and Texas have enacted kratom consumer protection regulations. Healthcare providers need to know if their state has passed bans or regulations, and what the regulations specify. A few localities in states where kratom is legal have established their own restrictions. Some examples include San Diego, California (sale or possession are illegal), Denver, Colorado (no sale for human consumption), Jerseyville, Illinois (banned entirely), Sarasota County, Florida (banned entirely), and Union County, Mississippi (banned entirely).³⁷

The Kratom Consumer Advisory Board is comprised of a scientist and pharmacist (C. Michael White, PharmD) and consumers who have been helped or harmed by kratom products.³⁸ They develop position statements and advise researchers, legislators, and advocacy groups about best practices regarding kratom use. The position statements can be accessed in the references and describe potential regulatory language and rationale behind preventing children from accessing kratom, the risks of 7-OH-MG products, proper labeling, and the need to register products that are being sold to consumers in the state to enforce safety regulations and good manufacturing practices.³⁸

This regulatory environment surrounding kratom should not extend to products with doses of 7-OH-MG that could never exist in nature. Emboldened by the DEA and the FDA’s inaction to date, newer products such as the “Press’d: The Hulk Blend” are combining 15 mg of 7-OH-MG with 15 mg of mitragynine pseudoindoxyl.³⁹ There is one product that contains only mitragynine pseudoindoxyl.⁴⁰ It is indefensible that these products could possibly be considered natural since mitragynine pseudoindoxyl does not exist in kratom leaves at all. Now, other semi-synthetic alkaloids of mitragynine are being created and placed in products such at 8- and 11-hydroxymitragynine and “Red-OH” with no published animal or human data.⁴¹ The HOPES research group at the University of Connecticut is actively cataloging a comprehensive list of 7-OH-MG, mitragynine pseudoindoxyl, 8-hydroxymitragynine, and “Red-OH” products on the market so states that register products sold in their state can assure that these drugs are excluded from sale. If the tianeptine debacle has taught us anything, it is that we need to identify products being sold as natural products and determine if they are truly reflective of nature.⁴²

Finally, new clouds are on the horizon with mitragynine and 7-OH-MG extracts that are being placed into candy formulations (popping crystals, noobs, chocolate bars, gummies, taffy, and ice cream cones), flavorings like strawberry, raspberry, mango, and grape, and sold with cute cartoon mascots.⁴³ The more kratom products resemble sweet treats, the greater the risk of children consuming them. The HOPES research group is also cataloging a comprehensive list of these products that could entice children so states that register products sold in their state can restrict their sales.⁴³

PAUSE AND PONDER: Does your practice state or municipality have regulations towards 7-OH-MG? Mitragynine? Kratom? Should it?

In this CE activity, we have shown that 7-OH-MG and mitragynine pseudoindoxyl relies entirely on opioid receptor effects, rather than impacting a balanced series of receptors like traditional kratom products do.^1,8,19,28,29 Preclinical studies suggest that 7-OH-MG has reinforcing effects that mitragynine (the most abundant alkaloid in traditional kratom products) does not have; this is a warning sign for its addiction potential.^28,29 Customer experiences with 7-OH-MG products suggest euphoric effects that mimic traditional opioids, faster tolerance and shorter duration of action, and faster onset with more severe withdrawal compared to traditional kratom.³² Until more is known about 7-OH-MG’s effects, shouldn’t customers be protected from accessing products that can potentially result in a lifetime of addiction? If nothing else, can we at least ensure that 7-OH-MG products are not classified as kratom products? If a consumer substitutes kratom for traditional opioids and accidentally experiences the euphoric effects from 7-OH-MG, it might be analogous to giving alcoholics a drink and restarting their cravings. If a wave of bad press about 7-OH-MG products falls under the umbrella of “kratom products,” both products could become Schedule I; a risk to consumers who rely on kratom to manage their opioid use disorder (OUD).

California is working on legislation that would protect their citizens from 7-OH-MG products.⁴³ In its legislation, kratom products would have a dose of 7-OH-MG that is a small fraction of total alkaloids in the product. This proposed California legislation can be a national model or can be emulated state by state.⁴⁴

What are health professionals’ responsibilities regarding 7-OH-MG products? The first is to be aware of changes in the kratom marketplace. Providers who have patients using traditional kratom products or who inquire about its use need to tell them that 7-OH-MG products—which they may call “7” or “7-OH”—are not kratom and could reinforce opioid addiction rather than provide relief. They should also educate patient’s that the U.S. FDA has approved therapies for OUD where the positive balance of benefits to risks are well known, augmenting that counseling providers can tell patients how to access services.⁴⁵ If people are addicted to 7-OH-MG products, they need treatment to overcome their K-SUD, just like they would for other opioid receptor agonists. Finally, health professionals should alert regulators and our legislators about emerging threats to our patients’ health and well-being so they can take action.

Cindy finished her research and scheduled an appointment to meet with Pete. She has reviewed all of the science, reconnected with her professor to clarify a few things, and also examined her state and local laws. She looked for articles, podcasts, and radio transcripts to find facts about local, state, and national trends. When Pete arrives, she is prepared to discuss the risks associated with 7-OH-MG. She tells him that “7” is not a natural product, explains why that is the case, and that it could be downright dangerous. Next, she discusses cost (which can be steep) and the fact that it isn’t covered by insurance. She expresses concern that we know little about its safety and gas station products are often labeled poorly or misleadingly. Finally, she tells Pete that it will not “fix” his problem with constipation. Kratom may be a potential option for some patients, but other FDA-approved options are available to support Pete that have proven clinical trial effects and would be better initial options to explore.

Cindy realizes that this is an opportunity to help Pete. She explains that he is having breakthrough pain, and it may be time for the multidisciplinary team to become more involved. Pete admits he has not been going to physical therapy as scheduled, and he blushes when she asks if he’s been taking a stimulant laxative (he hasn’t). Cindy takes some time to contact the primary prescriber, and they work with the physical therapist to develop a better treatment plan for Pete. That new plan does not include 7-OH-MG.

CONCLUSIONS

Products with 7-OH-MG and/or mitragynine pseudoindoxyl act solely through opioid receptors. Preclinical studies and human anecdotal experiences show 7-OH-MG provides euphoric effects that traditional kratom products (whole leaf or mitragynine extracts) do not. Given the known risks of OUD, 7-OH-MG and/or mitragynine pseudoindoxyl products should not be thought of, or listed as kratom and regulators should not transfer the hands-off attitude towards kratom to 7-OH-MG. It is inappropriate to have opioid receptor stimulators like 7-OH-MG or mitragynine pseudoindoxyl sold in gas stations, smoke shops, and over the internet without a prescription, limitations in dosage, and medical oversight.

Download CE Activity

If you’ve heard it once, you've probably heard it a dozen or more times: pharmacists are the most accessible healthcare resource. Most people live close to a pharmacy. A 2022 study reported 89% of persons in the United States (U.S.) live within five miles of a pharmacy and all but 3% are within 10 miles.¹ Despite being this accessible, pharmacies are closing in record numbers.^2,3 These closures are creating pharmacy deserts—communities in which residents must travel farther to access the nearest pharmacy to fill prescriptions—in communities in urban centers or with Black and Latine (see SIDEBAR) populations most at risk.^2,3

SIDEBAR: Latine or Latinx?

Americans have used many terms to describe individuals or groups who live in the United States and have Latin American roots. Traditionally, the word “Latino” has been used to describe males or males and females, and sometimes “Latina” has been used for females. The most widely used term, however, was “Hispanic” and included people of Spanish origin (i.e., from Spain). Several years ago, the term Latinx emerged as a gender-neutral, more inclusive term. Language, however, evolves, and some people with Latin American origins objected to the inclusion of the letter X. Older languages in Latin America did not include the letter X. Colonists forced indigenous people to add X into languages during the conquest. Its pronunciation is odd or unnatural in many dialects.

While Latinx is currently used more frequently in the academic literature, the term Latine is becoming more commonly accepted in the community. For the purposes of this continuing education activity, they are interchangeable.

Vaccines are one of the most successful interventions in public health in our generation. Worldwide, vaccines have prevented 154 million deaths since 1974.⁴ In the U.S., routine childhood vaccinations provided to children born between 1994 and 2023 have had an impressive impact. Within this population, they have saved $540 billion in direct costs and prevented more than 500 million illnesses, 32 million hospitalizations, and 1.1 million deaths.⁵

Immunizing for Influenza and COVID-19

Influenza and COVID-19 vaccines are examples of vaccines whose primary goal is to prevent severe disease and death. Influenza vaccine specifically has shown to decrease risk of intensive care admission (odds ratio [OR] = 0.74 (95% confidence interval [CI]: 0.58-0.93)) and death (OR = 0.69 (95% CI 0.52-0.92)) among adults hospitalized with influenza disease.⁶ An odds ratio less than 1.0 indicates a protective effect; therefore an OR of 0.74 indicates the influenza vaccine reduces the risk of an intensive care admission by 26%, and an OR of 0.69 indicates 31% less risk of death when hospitalized with influenza disease. The CI reflects there is 95% confidence the true risk of an intensive care admission is reduced by 7% to 42%, and the risk of death is reduced by 8% to 48%.  In the first year of use, primary COVID-19 vaccination prevented 14.4 million deaths.⁷ The 2023-2024 booster vaccines provided 51% and 36% effectiveness against hospitalization for the seven to 79 days post-vaccination in healthy non-immunocompromised and immunocompromised patients. Unfortunately, vaccine efficacy wanes significantly by four to six months in all people, but especially those who are immunocompromised, explaining the recommendations for boosters.⁸

Pharmacists, pharmacy technicians and interns, and pharmacies have become the most relied-upon resources for obtaining recommended vaccines, especially the COVID-19 and influenza vaccines. Sixty-eight percent of COVID-19 vaccines from September 2022 to September 2023 were administered in a pharmacy.⁹ More recently, these numbers have risen, with data showing that pharmacists provided 90% (23.5 million doses) of the 26.1 million doses of COVID-19 vaccines from August 31 through November 30, 2024.¹⁰ Data shows similar trends for adult influenza vaccinations at pharmacies, with growth from 49% in 2019 through 2020 steadily increasing each year; initial estimates (through November 2024) indicate that for the 2024-2025 season report, pharmacies have administered 64% of influenza vaccines.¹¹

Pharmacy’s response to the COVID-19 pandemic has amplified the pharmacist’s and pharmacy technician’s value and accessibility to providers, policymakers, and the public. Expanding the pharmacist’s clinical functions will only become more critical as the physician workforce continues to shrink through the coming decades. According to the Association of American Medical Colleges (AAMC), the U.S. is projected to face a physician shortage of up to 86,000 physicians by 2036, with the most significant shortage expected in primary care specialties.¹²

More than Immunizations

Beyond immunizing, the pandemic revealed the pharmacist’s valuable contributions involving point-of-care testing and follow-up care through treatments not only for COVID-19, but also for influenza, urinary tract infections, HIV, and contraceptives. The Centers for Disease Control and Prevention (CDC) recognized pharmacy’s contributions during the COVID-19 pandemic by stating, “The COVID-19 pandemic has demonstrated needed roles for the community pharmacist in an emergency, including continuity of provision of medications, providing preventive services, and ensuring health equity. Along with medication management, pharmacists provide infectious disease mitigation, point-of-care testing, and vaccinations.”¹³

The COVID-19 pandemic resulted in an excess burden of mortality in at-risk populations, precipitated by racial and ethnic disparities in health care access and use. While, as stated, 89% of Americans live within five miles of a pharmacy, heightened awareness of newly emerging pharmacy deserts in Black and Latine communities resulting in higher risk of morbidity and mortality disparities is needed.^1,3 Health Affairs published a pharmacy closure study in December 2024. It revealed that independent pharmacies were at greater risk for closure than chain pharmacies across all neighborhood and market characteristics. The authors hypothesized that independent pharmacies in predominantly Black and Latine neighborhoods would be at greatest risk for closure because they are more likely than chain pharmacies to serve populations insured through Medicaid or Medicare. The reason is that Medicaid and Medicare incentivize patients to use preferred pharmacy networks managed by pharmacy benefit managers. Because preferred networks often exclude independent pharmacies, this policy limits patient volumes and profits of independent (nonpreferred) pharmacies, thus potentially increasing their risk for closure. This may have created previous health disparities and may potentially exacerbate future disparities by worsening access and lowering adherence rates to medications and other therapies.^2,3

PUBLIC READINESS AND EMERGENCY PREPAREDNESS (PREP) ACT

The Public Readiness and Emergency Preparedness (PREP) Act is not new. Initially approved by Congress in 2005 and signed by then-President George W. Bush in 2005. The PREP Act authorizes the Secretary of Health and Human Services (HHS) to limit legal liability for losses relating to the administration of medical countermeasures such as diagnostics, treatments, and vaccines. In a declaration effective February 4, 2020, the Secretary of HHS invoked the PREP Act and declared Coronavirus Disease 2019 (COVID-19) to be a public health emergency warranting liability protections for covered countermeasures. The PREP Act is currently on its 12th amendment.¹⁴ The PREP Act defines a “covered person” to include licensed health professionals and other individuals authorized to prescribe, administer, or dispense covered countermeasures under state law, and other categories of persons identified by the Secretary in a PREP Act declaration.^14-16

The April 2020 amendment to the Act provided pharmacists federal authority to order and administer FDA-authorized COVID-19 tests. The August 2020 Amendment to the PREP Act expanded the definitions of covered diseases and covered persons. It expanded the categories of disease representing a public health emergency to include diseases resulting from “the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.” This allowed pharmacists to prescribe and administer, and interns to administer vaccines in accordance with the Advisory Committee for Immunization Practices (ACIP) to children 3 through 18 years old.^14-16

In the fall of 2020, the Secretary of HHS modified the Act twice more. In August, it added COVID-19 vaccines to the vaccines pharmacists and interns were permitted to administer. In September, notably, for the first time it included pharmacy technicians in the authority provisions, allowing them to administer childhood and COVID-19 vaccines to those aged 3 years and older. A year later, in August and September of 2021, the Act extended authorization covering pharmacy interns and technicians to administer seasonal influenza vaccination for those 19 years and older as recommended by ACIP. It also authorized pharmacists to prescribe and administer specific COVID-19 therapeutics, such as monoclonal antibodies, and interns and technicians to administer these products.^14-16 In July 2022, another amendment added the authority for pharmacists to prescribe nirmatrelvir/ritonavir tablets (Paxlovid).^14,16

As a public health crisis resolves, the PREP Act is amended to eliminate provisions no longer deemed necessary. HHS declared the Public Health Emergency was no longer in effect as of May 11, 2023, however COVID-19 was deemed to still present a “credible risk of a future public health emergency.” As the COVID-19 emergency was no longer at its peak, the 11th Amendment in May 2023 began to decrease the authority of pharmacists, interns, and technicians. Specifically, the 11th Amendment of the PREP Act extended authority through December 31, 2024, but the authorization would only allow pharmacists to order and administer, and pharmacy interns and technicians to administer COVID-19 and seasonal influenza vaccines to age 3 and over and COVID-19 tests. The authorization no longer covers all childhood vaccines but continues to allow pharmacists to prescribe nirmatrelvir/ritonavir tablets.¹⁵

Is the PREP Act Still Needed?

COVID-19 continues to cause significant illness and death and considered to present a credible risk of a future public health emergency. In 2024, the CDC’s COVID Data Tracker reported between 300 and 2500 deaths from COVID-19 each week.¹⁷ Congress delegated the ability to amend the PREP Act to the HHS Secretary. This motivated Xavier Becerra, the then HHS Secretary, to issue the 12th amendment to the PREP Act in December 2024.¹⁴ Effective January 1, 2025, it was amended to continue PREP Act coverage through December 31, 2029, barring any change from the HHS Secretary. This extension granted by the 12th amendment to the PREP act allows pharmacists, pharmacy interns, and technicians to continue providing essential services for seasonal influenza and COVID-19.¹⁴ These services include allowing pharmacists to prescribe and administer seasonal influenza and COVID-19 vaccines for those as young as 3 years of age (see SIDEBAR) in line with the ACIP recommendations (see Table 1). They still have the authority to prescribe nirmatrelvir/ritonavir tablets. Pharmacy interns and pharmacy technicians are also authorized under the Act to provide these two immunizations to these patients under the pharmacist’s supervision.

SIDEBAR: What’s Magic about Age 3?²¹

The PREP Act authorized administration of inactivated vaccines in children as young as 3 years of age. The minimum age of 3 years old was chosen because that is the age at which the vaccine administration process is the same as that employed for adults. Before age 3, the thigh is the preferred site because of the greater muscle mass.

Specifically, as these shots are all inactivated vaccines, the preferred site of administration, beginning at age 3 years, is the deltoid muscle. When administering inactivated vaccines, immunizers should inject them at a 90-degree angle into the deltoid muscle, avoiding the top 1/3 of the muscle and staying above the armpit. It is important to landmark the deltoid and use the recommended vaccine needle size to ensure efficacy and prevent shoulder injury related to vaccine administration (SIRVA).

Table 1.  PREP Act Requirements for Pharmacists, Pharmacy Interns, and Pharmacy Technicians^14,18

*FDA authorized COVID-19 vaccines: Novavax for those 12 years and older, Moderna and Pfizer BioNTech for those 6 months through 11 years. FDA approved COVID-19 vaccines: Moderna and Pfizer BioNTech for those 12 years of age and older.

The HHS Secretary decides to amend or declare the PREP Act based on a variety of factors. HHS gathers expert advice and public health data and assesses legal considerations by consulting with relevant stakeholders before issuing a declaration or amendment. The HHS Secretary must consider the many variables involved encouraging the use of countermeasures (interventions that help prevent or slow the spread of disease). These include the design, clinical testing, manufacturing, labeling, marketing, purchase, donation, dispensing, licensing, prescribing, and administering of the countermeasure. A determination of a public health emergency is different than a PREP Act declaration. If HHS determines a public health emergency exists, HHS can waive certain Medicaid, Medicare, State Children’s Health Insurance Program (CHIP), and Health Insurance Portability and Accountability Act (HIPPA) requirements. A PREP Act declaration may be made in advance of a public health emergency and may provide liability immunity for activities both before and after a declared public health emergency.

Public Health Emergencies vs PREP Act Declarations

A public health emergency determination or other emergency declaration is only required for immunity under the PREP Act if this is explicitly stated in the declaration.¹⁸ Therefore, when it is determined that there is no longer concern for significant COVID-19 related illnesses, it is likely that the Secretary of HHS will sunset this provision as well. Thus, it is very important that pharmacists, pharmacy interns, and pharmacy technicians continue to advocate for expansion of their immunization authority. This advocacy, specifically in states where full immunization authority is absent, will enhance immunization care to patients in need.

PAUSE AND PONDER: What does your state authorize pharmacists, pharmacy interns, and pharmacy technicians to provide and are there vaccine or age restrictions?

In addition to the vaccination authority, the Act continues to allow pharmacists to prescribe and administer, and for interns and technicians to administer under the pharmacist supervision, COVID-19 tests.¹⁴ Multiple types of COVID-19 tests are able to be used in the pharmacy. It is important for all immunizers and support staff to review the instructions on the specific tests carried in the pharmacy. Many tests (e.g., antigen, nucleic acid amplification tests [NAATs]) require nasal or nasopharyngeal sampling, but some NAAT tests may require oropharyngeal, sputum, or saliva sampling.¹⁹ Importantly, the Act continues to provide liability protection for those who provide these services (i.e. vaccines, tests) per the recommendations.¹⁴

ADULT VACCINATION UPTAKE POOR, PEDIATRIC RATES DECREASING

Although the 11th amendment of the PREP Act in May 2023 removed federal authority for pharmacists to provide routine childhood vaccines (other than seasonal influenza or COVID-19), many states have worked to expand their state laws to provide these authorities. As of January 2025, only one state, Delaware, does not authorize pharmacists to provide any vaccines to children under its state laws.^15,22-24 Currently, 42 states provide pharmacists authority to administer routine vaccines beyond influenza and COVID-19 to children younger than 12 years old. At this time, 36 states allow vaccines other than COVID-19 and influenza to be administered by a pharmacist to children 7 years of age or younger.^22-30 Many states currently have no minimum age for pharmacists to provide childhood vaccines. Further, pharmacists in most states can provide many routine vaccines to adults. It is important that pharmacists continue to educate and advocate for timely vaccination of children and adults and provide an accessible way for patients to easily obtain these vaccines, when authorized.

PAUSE AND PONDER: How do you routinely advocate and provide immunizations to patients? How could you improve?

Many adults do not know that they should receive any vaccines. Data from 2022 demonstrates that only 22.8% of adults received appropriate immunizations for age including influenza. Further concerning is that Black and Latine populations reported lower rates at 12.1% and 17%, respectively.³¹ When rates associated with individual vaccines were analyzed, tetanus vaccination in the past 10 years (59.2% of all adults) and pneumococcal vaccination in those 65 years and older (64%) were the highlights, having the best coverage. Some significant deficits included pneumococcal vaccination for high-risk adults (23%) and a single dose of recombinant zoster vaccination of individuals 50 years and older (25.6%).³¹ These data provide yet another reason to continue efforts to educate adult patients within your practice that they may need vaccines.

PAUSE AND PONDER: What can you do in your pharmacy to provide education to adult individuals about their needs for vaccinations?

Unfortunately, vaccine misinformation is rampant and has led to many children not receiving the vaccines they need. Survey data from those entering kindergarten suggests that overall immunization rates have dropped from 95% just a few years ago to overall 93%.³² Some parents are either avoiding some or all vaccinations or spacing them beyond what is recommended. This has been noted by a large increase in vaccine exemptions for children.^32-34 States and localities generally establish vaccination requirements for school attendance. They also develop conditions and procedures for exemptions from vaccine requirements, timeframes for submitting documentation, and conditional registration for students who need more time to be vaccinated. In the 2023-2024 academic year, 3.3% of children who prepared to enroll in kindergarten had at least one vaccine exemption overall. Thirty states had exemption rates higher than this with Idaho reporting 14.3% of children with at least one vaccine exemption. Of note, 93% of these exemptions were nonmedical in nature.³² Readers can find the exemption rates for their own states here in Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC11486350/

It is a problem when many individuals decide not to be vaccinated or to not have their children vaccinated, because when a community no longer maintains a high percent of a population protected (generally considered at least 90%), the population loses herd immunity.³⁵ Without herd immunity protecting a community population, the community will be susceptible to outbreaks of these vaccine preventable diseases.

Measles is a prime example of this phenomenon. Measles is a very contagious infection that requires about 95% of a population to be vaccinated to prevent spread in a community.³⁶ Recent data suggests that the percent of children entering kindergarten receiving two doses of MMR vaccination dropped below 95% (at 93.9%) in 2021-2022 and further decreased to 92.7% in 2023-2024.^{32, 34} We have begun seeing increases in measles cases again, with 284 cases (40% requiring hospitalization) reported in 2024.^35,37

The percentage of the population that needs to be vaccinated to achieve herd immunity depends on the disease. While herd immunity for measles requires about 95% of the population to be vaccinated, for polio the threshold is about 80%. It may take several years to determine herd immunity for a specific disease, and it will likely vary according to the community, the vaccine, the populations prioritized for vaccination, and other factors.

CONCLUSION

The December 2024 12th amendment of the PREP Act provided liability immunity for pharmacists, pharmacy interns, and pharmacy technicians to continue to provide COVID-19 and influenza vaccination and testing and treatment for COVID-19. The age at which these two immunizations have been expanded by the Act is for those 3 years and older. This age was chosen for these inactivated vaccines as the administration route is the same as it is for adults (i.e., intramuscular in the deltoid). Effective January 1, 2025, the 12th Amendment of the PREP Act Declaration was extended to continue coverage through December 31, 2029.

It is essential to have pharmacy personnel continue to advocate and provide easily accessible vaccines as pharmacists are the most accessible healthcare providers, as a pharmacy is within five miles of nearly 90% of the population. However, a potentially significant health disparity is developing as decreasing access is occurring due to pharmacy closures, especially independent pharmacies and those in Black and Latine communities. Policy makers should consider strategies to increase the participation of independent pharmacies in Medicare and Medicaid preferred networks managed by pharmacy benefit managers and to increase public insurance reimbursement rates for pharmacies that are at the highest risk for closure.

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INTRODUCTION

More than 72 million individuals of reproductive age (15 to 49 years old) live in the United States (U.S.), and about 43 million of them are at risk of unintended pregnancy.¹ This means they are sexually active and could experience unwanted pregnancy if they and their partners fail to use contraceptives consistently and correctly.

Here is a striking but under-reported fact: about one in two pregnancies in the U.S. is unintended (i.e., mistimed or unwanted at the time of conception).² Compared to intentional pregnancies, people experiencing unintended pregnancy experience more mental health problems, have less stable romantic relationships, and sometimes delay initiation of prenatal care.³ Ideally, those who unintentionally conceive should ideally be in good health and ready to care for a new child, but sometimes that is not the case.

Children born as a result of unintended pregnancies are at an elevated risk of experiencing both mental and physical health challenges and are more likely to struggle in school.³ While the overall rate of unintended pregnancies is on the decline, disparities based on factors such as race/ethnicity, age, income, and education level persist.³

It is crucial to implement interventions that promote the use of contraception methods to prevent unintended pregnancies. While over the counter (OTC) options for pregnancy prevention exist, hormonal methods requiring a prescription (pill, patch, ring, and injection) are more effective than OTC products, withdrawal, or fertility-awareness methods for pregnancy prevention.⁴ Recent laws make it possible for pharmacists to prescribe hormonal contraceptives in some states, increasing access to these more effective therapies.

Note that this activity will employ the terms "woman/women" to align with the biological expectations of ovulation.

Understanding the Menstrual Cycle

The length of a woman’s menstrual cycle is a commonly misunderstood concept. While most people consider a natural 28-day cycle “normal,” this is only true for about 13% of women.⁵ The first day of menstrual bleeding is considered cycle day 1 and cycles range from about 21 to 40 days in length.

Hormone levels regulate the menstrual cycle. The pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which promote ovulation and release of estrogen and progesterone from the ovaries.⁶ This hormone fluctuation splits the menstrual cycle into three phases; note that the timeframes described below are approximate length based on a 28-day cycle⁶:

• Follicular phase (before egg release)
  • Lasts from cycle day 1 to ovulation
  • FSH levels rise to recruit a small group of follicles for growth and development
  • Between days 5 to 7, one follicle dominates and secretes estradiol to stop menstrual flow
• Ovulatory phase (egg release)
  • Occurs on or around day 14
  • Sustained FSH levels cause an LH surge about 28 to 32 hours before the dominant follicle ruptures, also known as ovulation, releasing the mature oocyte (egg)
• Luteal phase (after egg release)
  • Lasts from ovulation to the last day of the cycle
  • Remaining luteinized (matured) follicles become the corpus luteum, which produces progesterone to prepare the uterus for embryo (fertilized egg) implantation

Following the luteal phase, if no egg is fertilized or the egg does not implant, the corpus luteum degenerates after 14 days, estrogen and progesterone levels drop, and a new menstrual cycle begins.⁶ However, if a fertilized embryo is implanted, the cells around the embryo produce human chorionic gonadotropin (HCG). HCG maintains the corpus luteum, which continues to produce progesterone until the fetus can produce its own hormones. Pregnancy tests detect an increase in HCG in the blood or urine, indicating a fertilized embryo is present.⁶

PHARMACY-BASED HORMONAL AND EMERGENCY CONTRACEPTIVES

Contraception refers to the strategies employed to prevent pregnancy after sexual intercourse, which can be categorized into two main approaches⁷:

1. Inhibiting the encounter of viable sperm with a mature ovum, achieved through methods such as barriers or ovulation prevention
2. Preventing the implantation of a fertilized ovum in the endometrium, accomplished through methods that create an unfavorable uterine environment

It is crucial for sexually active individuals to be well-informed about the various contraceptive options available. This knowledge is essential in assisting patients in effectively preventing unintended pregnancies.

This activity will only discuss the birth control methods that pharmacists are directly involved in prescribing.

Hormonal Contraceptive Basics

As the name implies, hormonal contraceptives employ hormones—specifically, progestins and estrogens—to prevent pregnancy.⁷ Hormonal contraceptives do not protect patients from sexually transmitted infections, including human immunodeficiency virus, and this is a point that pharmacists need to stress at every visit. Estrogens’ role in birth control is to stabilize the endometrial lining and provide cycle control. However, estrogens also suppress FSH release from the pituitary gland to help block the LH surge and prevent ovulation. Progestins provide most contraceptive effect. They block the LH surge, which inhibits ovulation. Progestins also thicken cervical mucus to⁷

• prevent sperm penetration
• slow tubal motility
• delay sperm transport
• induce endometrial atrophy (thinning), reducing its receptivity to embryo implantation

Achieving the right balance between progestogens and estrogens is vital in hormonal contraceptives. Some hormonal contraceptives contain only a progestin, while others combine an estrogen and a progestin.⁷ Importantly, estrogen alone—or “unopposed estrogen”—does not protect against pregnancy and pose significant safety concerns. Patients with an intact uterus who take unopposed estrogen are at risk of cancer, endometrial hyperplasia, polyps, endometriosis, and adenomyosis.⁸

PAUSE AND PONDER: What is the difference between a CHC, a COC, and a POP?

Combined hormonal contraceptives (CHCs)—any contraceptive containing both an estrogen and progestin—are not appropriate for women⁷

• older than 35 years who smoke
• with obesity (body mass index 30 or greater)
• with untreated hypertension (greater than 160/100 mm Hg)
• with migraines (especially with aura)
• at risk for deep vein thrombosis

The estrogen component of most CHCs is ethinyl estradiol.⁷ Many different progestins of differing androgenicity and similarity to testosterone exist, but no evidence suggests that a particular progestin is superior to others. Traditionally, experts classified progestins into “generations” based on parent compound and decade of development, but data shows this is not clinically useful.⁷

A woman can start CHCs at any time during her cycle if it is reasonably certain that she is not pregnant.⁹ If a patient starts CHCs within the first five days of menstrual bleeding, no additional protection is needed, but if it has been longer than five days from the start of menses, she should abstain from intercourse or use backup contraception for the next seven days.⁹ Table 1 outlines missed dose guidance for all contraceptive types.

Table 1. Missed Dose Guidance for Contraceptives^7,10,11

ASAP, as soon as possible; COC, combined oral contraceptive; EE/E, ethinyl estradiol/etonogestrel; POP, progestin-only pill; SAEE, segesterone acetate/ethinyl estradiol.

Combined Oral Contraceptives

Combined oral contraceptives (COCs)—meaning oral products containing both an estrogen (e.g., ethinyl estradiol) and a progestin (e.g., norethindrone, levonorgestrel, norgestimate)—come in many forms. COCs are about 91% effective, meaning that 9 of 100 women will become pregnant in a year with typical use.¹² A major distinction in product selection is monophasic versus multiphasic⁷:

• Monophasic COCs contain the same amounts of estrogen and progestin for 21 days, followed by seven days of placebo
• Multiphasic COCs—including bi- and triphasic regimens—contain variable amounts of estrogen and progestin for 21 days, also followed by a 7-day placebo phase

Monophasic and multiphasic COCs boast similar safety and efficacy profiles, so product selection relies on hormonal content, patient-preference, and coexisting conditions.⁷ Women should typically initiate a COC containing 35 mcg or less of ethinyl estradiol and less than 0.5 mg of norethindrone (or an equivalent).⁷ Estradiol levels control the incidence of breakthrough bleeding. Few patients require doses of ethinyl estradiol greater than 35 mcg daily to prevent breakthrough bleeding. While some clinicians advocate for starting patients at the lowest possible estradiol dose to minimize risks, data suggests that 10 to 20 mcg of ethinyl estradiol daily is no safer than the 35-mcg dose and lower doses are associated with more breakthrough bleeding.⁷

Monophasic COCs are preferred over multiphasic upon initiation, as adverse effects (AEs) are easier to identify and manage. Monophasic COCs also allow for easy cycle extension (continuing the active moiety to bypass a period, an indication for which pharmacists are not authorized to prescribe) by simply skipping the placebo week and starting the next pack of active pills. When attempting this with multiphasic regimens, the variation in drug levels between phases often leads to breakthrough bleeding.⁷

Extended- and continuous-cycle COCs contain 84 days of active hormone tablets followed by seven days of inactive tablets, which may be more convenient with fewer AEs.⁷ Extended-cycle COCs are commercially available. Of note, some patients skip the 7-day placebo week of monophasic 28-day COCs to mimic extended-cycle products, but pharmacists are only legally authorized to prescribe hormonal contraceptives as indicated. Continuous-cycle COCs shorten the pill-free interval (e.g., two to four days versus seven days), thus reducing period-related symptoms. Patients using extended- and continuous-cycle regimens have fewer menstrual cycles annually, which is helpful for women with severe premenstrual syndrome (PMS), dysmenorrhea (menstrual cramps), and menstrual migraines.

Progestin-Only Pills

Progestin-only pills (POPs)—“minipills”—contain 28 days of active hormone (norethindrone or drospirenone) per cycle.⁷ They are generally less effective than COCs and associated with irregular, unpredictable menstrual bleeding. Patients must take POPs at approximately the same time (within three hours) every day for effective pregnancy prevention. The progestin dose in POPs is about one-third of that in COCs, resulting is less consistent suppression of ovulation. This leaves women at greater risk of breakthrough bleeding and ectopic pregnancy—pregnancy outside the uterus—because women on POPs often continue to ovulate regularly.⁷

Despite being less effective, POPs are appropriate for certain women. Postpartum women, for example, can experience hypercoagulability, and should avoid CHCs for at least 30 to 42 days postpartum due to risk of venous thromboembolism. Therefore, those who take contraceptives commonly take POPs.⁷ Women who breastfeed should also avoid CHCs, as the estrogen component can affect lactation, making POPs a better option.

POPs can be started at any time during a woman’s cycle if it is reasonably certain she is not pregnant.⁹ If a patient starts POPs within the first five days of menstrual bleeding, she need not use additional protection , but if it has been longer than five days from the start of menses, she should abstain from intercourse or use backup contraception for the next two days.⁹

ORAL CONTRACEPTIVE TAKEAWAYS:

• COCs: Initiating a monophasic formulation containing 30 to 35 mcg of ethinyl estradiol and less than 0.5 mg of norethindrone (or an equivalent) offers the best chance of establishing a consistent menstrual pattern without raising AE risk. If patients experience estrogen- or progesterone-related AEs (listed in Table 2), dose adjustment is warranted.
• Extended- or continuous cycle: Patients have fewer menstrual cycles each year, making them ideal for patients with severe PMS, dysmenorrhea, or menstrual migraines.
• POPs: Less effective than COCs, but appropriate for patients within 42 days postpartum and women who breastfeed, as estrogen can affect lactation.

Table 2. Hormone-Related Adverse Effects¹³

Non-Oral Hormonal Contraceptives

Some patients—particularly those who struggle with daily adherence to oral therapies—may benefit from alternative delivery mechanisms administered less frequently, including transdermal patch, vaginal ring, and injectable contraceptives.

The only transdermal CHC patch available in the U.S. contains ethinyl estradiol and norelgestromin (norgestimate’s active metabolite). The transdermal patch has comparable efficacy to COCs.¹² It may be less effective, however, for patients weighing more than 198 lbs (90 kg).¹⁴ Patients apply the patch to the abdomen, buttocks, upper torso, or upper arm at the beginning of the menstrual cycle, avoiding areas where the patch could be rubbed by tight clothing.¹⁴ Patients replace the patch once weekly for 3 weeks, followed by a patch-free week. The patch is formulated to release hormones for nine days, allowing a 48-hour grace period for adherence.¹⁴

The CHC patch’s adverse effects are similar to those of COCs, but some patients experience application-site reactions. Patients can prevent these reactions by rotating application sites. Dysmenorrhea and breast discomfort are also possible, as the patch causes higher estrogen exposure compared to COCs.¹⁴

Vaginal ring contraceptives offer excellent cycle control, as patients can insert and remove them, and fertility returns rapidly after removal.¹⁵ Two vaginal ring contraceptives are available:

• an ethinyl estradiol/etonogestrel (EE/E) ring that patients replace monthly
• a segesterone acetate/ethinyl estradiol (SAEE) ring that patients replace yearly

The EE/E vaginal ring delivers 0.015 mg of ethinyl estradiol and 12 mcg of etonogestrel (desogestrel’s active metabolite) every 24 hours.¹⁶ Estrogen exposure with the EE/E ring is lower than that associated with COCs, so incidence of estrogen-related adverse effects is also decreased. Local reactions, like vaginal irritation and discharge, are more common.¹⁶ The SAEE vaginal system is slightly larger in diameter than the EE/E ring and contains two drug reservoirs delivering 0.15 mg and 13 mcg of segesterone and ethinyl estradiol, respectively, every 24 hours.^15,10 The SAEE ring’s most common adverse effects are headache/migraine, nausea, vomiting, vaginal infections, abdominal pain, dysmenorrhea, vaginal discharge, urinary tract infection, breast discomfort, bleeding irregularities, diarrhea, and genital itching.¹⁰

To insert a vaginal contraceptive ring, patients should compress the ring between the thumb and index finger, then push the ring into the vagina.^16,10 There is no danger of inserting too far; the cervix will prevent the ring from traveling up the genital tract. Additionally, precise ring placement is not an issue, as the hormones are absorbed anywhere in the vagina. Patients should leave the ring in place for three weeks, then remove it for one week.

If using the EE/E monthly ring, patients should discard the ring (but not flush it down the toilet) after removal and insert a new one on the same day of the week as the previous cycle.¹⁶ Alternatively, the same SAEE ring can be used for up to one year. During the ring-free week, patients should store the SAEE ring only in the provided case away from children, pets, and extreme temperatures.^15,10 They should also wash the ring after removal and again before reinsertion using mild soap and water and pat dry with a clean cloth or paper towel. Patients should never use the same SAEE ring for more than 13 menstrual cycles.^15,10

If a vaginal contraceptive ring is removed from the vagina, intentionally or otherwise, no backup contraception is needed if the patient reinserts the ring within three hours for the EE/E ring and two hours for the SAEE ring.^16,10 If the ring remains out of the vagina for longer than these recommended time periods, backup contraception (e.g., male condoms, spermicide) is recommended for seven days after ring reinsertion. Patients should also avoid oil-based lubricants, as these can decrease the effectiveness of vaginal contraceptive rings.

Both vaginal ring systems carry risks for toxic shock syndrome (TSS), a rare, potentially life-threatening vital organ failure caused by bacterial infection.^16,10 Items that remain in the vagina for an extended period of time are implicated in TSS because bacteria can be trapped in the vagina and enter the uterus via the cervix or objects in the vagina can also cause tiny cuts through which bacteria can enter the bloodstream. Advise patients to seek medical attention if they experience signs/symptoms of TSS¹⁷:

• nausea or vomiting

• sudden high fever and chills
• watery diarrhea
• rash resembling a bad sunburn or red dots
• dizziness, light-headedness, or fainting
• hypotension
• red eyes (conjunctivitis)
• peeling on the soles of feet or palms of hands

Depo-medroxyprogesterone acetate (DMPA) is a longer-lasting injectable contraceptive injected every three months either intramuscularly into the gluteal or deltoid muscle or subcutaneously into the abdomen or thigh.¹⁸ This eliminates daily adherence concerns. DMPA is about 94% effective with typical use.⁹ Note that Connecticut law prohibits pharmacists from administering DMPA injections without a collaborative practice agreement, but patients may self-administer DMPA subcutaneously if desired and indicated.

Injection timing is somewhat flexible. Early DMPA injection is safe if women cannot follow routine intervals, and patients can inject up to two weeks late without requiring back-up contraception.¹⁸ Women who are more than two weeks late, however, should use back-up contraception for seven days after receiving the injection. Return to fertility may be delayed six to 12 months after discontinuation, so DMPA is not recommended for women desiring pregnancy in the near future.¹⁸

DMPA’s most common adverse effects are weight gain, decreased bone mineral density, and bleeding irregularities (e.g., spotting, prolonged bleeding, amenorrhea).¹⁸ DMPA carries a Boxed Warning indicating patients should not use the drug for more than two years due to bone mineral density loss, which may be irreversible.¹⁸ Patients should only use DMPA for more than two years if all other contraceptive methods are inadequate. Ensure patients are adequately trained to self-inject DMPA before leaving the pharmacy.

Emergency Contraceptives

Two oral emergency contraceptives (ECs) are currently available: a single dose of progestin (levonorgestrel 1.5 mg) or an anti-progestin (ulipristal acetate 30 mg).⁷ Levonorgestrel is available over the counter, while ulipristal requires a prescription.^19,20 Neither of these is abortifacient (i.e., they do not end an existing pregnancy), rather they work by blocking or delaying ovulation.

Women should take oral EC as soon as possible following unprotected intercourse, levonorgestrel within 72 hours and ulipristal acetate within five days.^19,20 Repeat levonorgestrel use shows no serious adverse effects, but studies have not examined repeat use of ulipristal acetate.⁷ Upon prescribing emergency contraception, pharmacists should evaluate women for long-term contraceptive eligibility to prevent repeat use of EC.

EC may alter the next expected menses.^19,20 Patients whose cycles are delayed more than one week should test for pregnancy. Additionally, women who become pregnant after using EC who experience lower abdominal pain should be evaluated for ectopic pregnancy (pregnancy occurring outside the uterus, most often in the fallopian tube).^19,20

PAUSE AND PONDER: Where can you find the living document called the United States Medical Eligibility Criteria (U.S. MEC) for Contraceptive Use and how often should you review its contents? (Note that some questions in the post-test will require you to access this document, so you must review it thoroughly.)

ELIGIBILITY AND PRESCRIBING

CDC Eligibility Criteria

The CDC publishes the United States Medical Eligibility Criteria (U.S. MEC) for Contraceptive Use to guide safe use of contraceptive methods for women with various medical conditions and other characteristics.²¹ The most current version of these guidelines (as of February 2024) can be found at https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html. Appendix A of this activity includes the entire U.S. MEC and the 2020 update. The CDC has also created a summary chart, included in Appendix B, and pharmacists should note that the summary chart is a convenience that does not replace a responsibility to access the entire document when necessary. Pharmacists actively prescribing hormonal contraceptives should regularly monitor for updates to this living document.

The U.S. MEC includes recommendations for contraceptive use based on patient characteristics or medical conditions.²¹ While many off label uses exist for contraceptives, these CDC recommendations apply only to these products’ indicated use to prevent pregnancy.

Four categories of medical eligibility criteria for contraceptive use exist within the U.S. MEC:

• Category 1: conditions for which no restrictions exist for use of the contraceptive method
• Category 2: conditions for which the advantages of using the method generally outweigh the theoretical or proven risks; the method can generally be used, but careful follow-up might be required
• Category 3: conditions for which the theoretical or proven risks usually outweigh the advantages of using the method; use is not recommended unless other more appropriate methods are not available or acceptable, so condition severity and the availability, practicality, and acceptability of alternative methods should be considered, and careful follow-up is required
• Category 4: conditions that represent an unacceptable health risk if the contraceptive method is used

Be mindful that provision of a contraceptive method to a woman with a condition classified as category 3 requires careful clinical judgement and access to clinical services that may be unavailable to pharmacists. Referral may be needed. Pharmacists should never prescribe a hormonal contraceptive method to a patient with a category 4 health condition related to its use.

Pharmacists should also take note of whether continuation criteria exist for the product prescribed.²¹ Continuation criteria is clinically relevant when a medical condition develops or worsens during use of a contraceptive method. When risk categories differ for initiation and continuation, the differences are noted in the Initiation and Continuation columns. When these distinctions are not indicated, the category is the same for initiation and continuation of use.²¹

Additionally, these categories only concern safety, but many other factors must be considered when choosing a contraceptive method. Classification as a category 1 means that the method can be used with no regard to safety but does not necessarily mean that method is the best choice for that patient. Consider other factors, including effectiveness, availability, and acceptability.

Determining Pregnancy Status

The Centers for Disease Control and Prevention (CDC) recognizes that routine pregnancy testing for women is not necessary before the initiation of contraception in all cases. Based on clinical judgment, healthcare providers can omit a pregnancy test if a woman has no signs or symptoms of pregnancy and meets any of the following criteria²¹:

• Is fewer than seven days after the start of normal menses
• Has not had sexual intercourse since the start of last normal menses
• Has correctly and consistently used a reliable contraception method
• Is fewer than seven days after spontaneous or induced abortion
• Is within four weeks postpartum
• Is fully or nearly-fully breastfeeding (exclusively or at least 85% of feeds), amenorrhoeic, and less than six months postpartum

Screening Documents Simplify the Process

A prescribing pharmacist must assist the patient in completing a screening document for hormonal contraceptives or emergency contraceptives, as applicable. These and all documents related to prescribing of hormonal contraceptives by pharmacists in the state of Connecticut are available at the Department of Consumer Protection’s (DCP) website: https://portal.ct.gov/DCP/Drug-Control-Division/Drug-Control/Drug-Control---Pharmacist-Contraceptive-Prescribing. Prescribing pharmacists are responsible for ensuring their pharmacies use the most current version of all screening documents at all times.

When an individual requests a hormonal contraceptive, pharmacists must first determine the patient’s age. If the patient is 18 years or older, the pharmacist may continue to prescribe with this guidance, but if the patient is younger than 18 years, the pharmacist may only issue a prescription upon confirming the patient has previously been prescribed a contraceptive by another provider through one of the following means:

• With the patient’s permission, contact the office or clinic where the patient visited a healthcare provider via telephone, facsimile, or shared health record system
• With the patient’s permission, contact the pharmacy that previously dispensed a contraceptive prescription to the patient via telephone, facsimile, or shared health record system
• Other acceptable documentation or evidence that demonstrates the patient has received prescription contraceptives (e.g., visit summary from the clinic that prescribed it, old prescription package/label)

The pharmacist must keep an electronic or written record of the action taken to confirm prior prescription for a minimum of 3 years. Whether prescribing a continuation of hormonal contraceptive therapy or initiating a new one, confirm the patient has been seen by a provider within the last 3 years either through written documentation (e.g., a visit summary) or contacting the office or clinic with the patient’s permission. Without this confirmation, pharmacists may not prescribe hormonal contraception.

Individuals with obesity (body mass index 30 kg/m² or greater) and patients using drugs that inhibit CYP3A4 (e.g., bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John’s wort, topiramate, efavirenz, lumacaftor) may experience decreased efficacy with EC.²¹ Patients ineligible for EC prescribing include those who

• are confirmed pregnant (though no harm to the woman, the course of her pregnancy, or the fetus if EC is inadvertently used is known to exist)
• have undergone bariatric surgery that may affect EC absorption (e.g., Roux-en-Y gastric bypass, biliopancreatic diversion); an emergency intrauterine device may be more appropriate

If a patient seeking EC is deemed ineligible for prescribing, the pharmacist should not prescribe the EC, refer the individual to a primary care provider (PCP), and document the reason(s) for refusal on the screening documents. If the patient has no PCP, the pharmacist should provide information regarding local providers.

Hormonal Contraceptive Screening and Prescribing

Upon determining patient eligibility, have the patient complete the Connecticut Hormonal Contraceptive Self- Screening Questionnaire found on the DCP website. The questionnaire addresses

• patient demographics (e.g., insurance status, allergies, preferences)
• background information (e.g., last menstrual period, history of contraceptive use)
• medical history (e.g., smoking status, preexisting conditions)
• pregnancy status

Review this screening tool with the patient and clarify responses if needed. If a patient is requesting CHCs or they are recommended, measure and record the patient’s seated blood pressure. If the patient does not complete the questionnaire, a pharmacist cannot issue the prescription. Pharmacists should keep the completed questionnaire on file for at least three years. Patients must fill out a new questionnaire at least once every 12 months, but pharmacists can request this more frequently if desired.

Pharmacists should then use patient questionnaire responses to follow the Standard Procedures Algorithm for Connecticut Pharmacist Prescribing of Contraceptives found on the DCP website. This algorithm, with its clinical assessment sections summarized in Figure 1, assists in screening for red flags requiring provider referral. Pharmacists should access the complete document on the DCP website before attempting to take the post-test.

Figure 1. Simplified Assessment Sections of the Algorithm for Contraceptive Prescribing

*Anticonvulsants, antiretrovirals, antimicrobials, barbiturates, herbs and supplements, including but not limited to: carbamazepine, felbamate, phenobarbital, lamotrigine, oxcarbazepine, ritonavir, primidone, griseofulvin, St. Jonh’s wort, topiramate, phenytoin, lumacaftor/ivacaftor, and rifampin/rifabutin.

Pharmacists should pay special attention to steps 6 and 7 of the Standard Procedures Algorithm (and take a moment to access it now). It describes counseling points on starting hormonal contraception, managing expected and unexpected side effects, and appropriate adherence. Not that Step 7 is critical! Women need to be reminded about routine healthcare and sexually transmitted infection prevention. And the pharmacist’s job isn’t done until the paperwork is filed.

If hormonal contraceptives are not clinically appropriate based on the treatment algorithm, the pharmacist should refer the patient to a practitioner, not prescribe the hormonal contraceptive, and document the reason(s) for refusal on the screening documents. The State of Connecticut provides a Pharmacist Referral and Visit Summary template that may be used for this purpose. If hormonal contraceptives are clinically appropriate, pharmacists may prescribe a total of no more than 12 months including initial filling of the prescription along with refills. Refills may be transferred to another pharmacy if desired, as a pharmacy that does not have a prescribing pharmacist may dispense a prescription written by a prescribing pharmacist. Pharmacies may not, however, fill prescriptions written by pharmacists authorized to prescribe in other states but not in Connecticut.

Emergency Contraceptive Screening and Prescribing

To be eligible for a self-administered EC prescription, an individual must complete the Connecticut Emergency Contraception Self-Screening Questionnaire found on the DCP website indicating that the last day of unprotected intercourse was within the previous five days (120 hours). Pharmacies may create and use an electronic version of this self-screening tool if the collection of patient information and assessment process is at minimum identical to the state-provided questionnaire. The pharmacist must review the screening tool with the patient, clarify responses if needed, and measure and record the patient’s seated blood pressure.

Pharmacists should consider the following when choosing between levonorgestrel and ulipristal acetate for EC:

• Levonorgestrel may be less effective than ulipristal acetate for women who weigh more than 165 lbs
• Levonorgestrel may be preferable for patients who need EC due to missed or late administration of existing hormonal contraception
• Starting hormonal contraceptives immediately after taking ulipristal acetate (within 5 days) may make it ineffective
• Insurance may still cover OTC levonorgestrel if a pharmacist prescribes the product
• Ulipristal acetate is more effective than levonorgestrel if more than 72 hours have passed since the last day of unprotected intercourse

Prescriptions for EC may not have any refills. Upon prescribing EC, counsel patients on the product’s proper use and potential adverse effects and provide written educational materials. The pharmacist must also notify the patient’s PCP and obstetrician/gynecologist (OB/GYN) with the patient's consent. If the patient does not have a PCP, the pharmacist should counsel the patient regarding the benefits of establishing such a relationship and, upon request, provide information regarding local providers. The pharmacist should also counsel the patient regarding the importance of preventive care, including routine well-woman visits, testing for sexually transmitted infections, and pap smears. Additionally, consider whether patients should also be evaluated for ongoing hormonal contraception, especially if they visit the pharmacy repeatedly for EC.

STICKING TO THE LAW

PAUSE AND PONDER: Are you ready for pharmacy-based contraceptive prescribing? Where will you maintain your documentation?

Documentation and Recordkeeping

Pharmacies must maintain appropriate records of hormonal contraceptive and EC prescribing:

• All completed screening documents must be maintained at the prescribing pharmacy in the same manner as the prescription itself for at least three years.
• All records created as part of the prescribing process must be maintained for at least three years and be readable retrievable and provided to DCP within 48 hours

Prohibited Acts

A prescribing pharmacist shall not

• prescribe any hormonal contraceptive or EC in an instance where the screening document for hormonal contraceptive or screening document emergency contraceptives indicates that referral to a practitioner is clinically appropriate
• prescribe any hormonal contraceptive or EC without a completed screening document for hormonal contraceptive or completed screening document for emergency contraceptive, as applicable
• issue a prescription for a total supply period exceeding 12 months based on the directions of use provided on the prescription
• prescribe any hormonal contraceptive or EC outside of the approved use stated in the product’s FDA-approved package insert
• prescribe a medical device, with or without hormonal contraceptives, that is implanted by a practitioner for the purpose of preventing pregnancy, including intrauterine and implantable devices

Pharmacy Technician and Intern Involvement

Pharmacy technicians who have completed an approved training course for prescribing of hormonal contraceptives may, at the pharmacist's request, assist the pharmacist in prescribing a hormonal contraceptive by:

• providing the screening document to the patient
• taking and recording the patient's blood pressure
• documenting the patient's medical history

A registered pharmacist intern may prepare a prescription for a hormonal contraceptive under the direct supervision of a trained prescribing pharmacist, but a pharmacist authorized to prescribe under this protocol must review, approve, and sign the prescription before the prescription is processed or dispensed.

CONCLUSION

Pharmacist prescribing removes significant barriers to patient access and use of hormonal contraceptives and EC to prevent pregnancy especially for those with limited access to healthcare services or busy schedules. More than 90% of Americans live within five miles of a pharmacy, making pharmacists the most accessible healthcare professionals and perfectly positioned to improve contraceptive access.²² Pharmacist involvement can lead to better education and counseling on contraceptive options, promoting informed decision-making and improving therapy uptake and adherence.

APPENDIX A – CDC US Medical Eligibility Criteria for Contraceptive Use, 2016

APPENDIX B – CDC US Medical Eligibility Criteria for Contraceptive Use, 2016, SUMMARY CHART

Download CE Activity

“I believe that misinformation is now our leading cause of death... People are distracted and misled by the medical information Tower of Babel.”¹ Dr. Robert Califf, Commissioner, Food and Drug Administration.

INTRODUCTION

The world faced a deadly infection running rampant. Some health experts believed that a vaccine could confer protection against the infection, but this view was met with skepticism and distrust. Misinformation spread within and beyond the scientific community and debates about the inoculation’s safety and efficacy emerged on many fronts. Physicians observed infections in some vaccinated individuals and opponents began speaking publicly about their distrust of the vaccine. The use of an animal source for the vaccine contributed to the belief that miniature cow heads could grow from sites of vaccination. Vaccine hesitancy and fear grew among the public.²

While this may sound like recent events, it describes the atmosphere surrounding the development of a vaccine for smallpox in 1796.² Many years later, the increasing popularity of television [like social media today] exaggerated fears of smallpox vaccination by broadcasting both descriptions and visual footage of the rare instances in which the smallpox vaccine produced severe adverse effects.² This messaging skewed perceptions about the vaccine’s risk/benefit profile and further eroded trust in the scientific community. Overall, these misperceptions delayed the worldwide eradication of smallpox by more than 200 years.²

This narrative illustrates that misinformation is not a recent phenomenon. Examples can be cited going back thousands of years.³ More significantly, it demonstrates misinformation’s destructive consequences. Recently, misinformation rose to unprecedented prominence with the COVID-19 pandemic, with the Director of the International Fact Checking Network calling COVID-19 “the biggest challenge fact-checkers have ever faced.”⁴

Health misinformation can be harmful. U.S. Surgeon General Dr. Vivek Murthy has stated, “Misinformation takes away our freedom to make informed decisions about our health and the health of our loved ones. Simply put, health misinformation has cost us lives.”⁵

Health misinformation can influence political, economic, and social well-being. People can become confused and anxious when faced with contradictory information, and this is especially dangerous during a public health crisis.^5,6 It can expose patients to wasteful and harmful products and procedures, delay treatment with a more scientifically based therapy, and divide families and communities.⁶

Pharmacists, of course, also have a role during a healthcare crisis and can be either another source of misinformation or a resource to clarify and refute poor advice. This continuing education activity will examine some recent efforts by governmental and non-governmental organizations to limit information that is contrary to mainstream medical advice and the sanctioning (or lack thereof) of healthcare providers for encouraging such therapies. Various approaches by governmental agencies to deal with conflicting information have raised legal issues when trying to restrict the free flow of information.

Disclaimer: Please note that the examples referred to in this lesson were chosen based upon their high-profile and impact and should not be interpreted as representing any political commentary, agenda, or endorsement by the author or publisher. It is acknowledged that “misinformation” is hard to characterize, and a consensus can shift as more data are developed. One should also not infer that the examples represent a deliberate intent to deceive by their sponsors.

PAUSE AND PONDER: What should be the role for pharmacists and pharmacy technicians in mitigating the impact of misinformation?

MISINFORMATION

Misinformation is frequently used as a catch-all term for related concepts such as disinformation, ignorance, rumor, and conspiracy theories, often resulting in different interpretations and imprecise definitions.⁷ Misinformation is often distinguished from disinformation on the basis of intent. In this context, misinformation is used to describe information that is unintentionally erroneous (e.g., mistakenly repeated or due to ignorance) while disinformation is information that is deliberately intended to mislead or deceive (e.g., malicious, fraudulent, or for propaganda).⁷

Health misinformation has been defined as information that is false, inaccurate, or misleading according to the best available evidence at the time (emphasis added).⁵ This definition recognizes that the accuracy and recognition of information can change as new data or experiences emerge. Although not health related, one needs to look no further than the writings of Galileo to find an example of information that was once condemned and humiliated. Formerly branded a heretic for claiming that the earth rotated around the sun, Galileo’s ideas later became the fundamental basis for astronomy and space travel.⁸                                   

Public health recommendations changed rapidly during the progression of the COVID pandemic and resulted in confusion among the public and distrust of public health agencies. A recent survey found that 60% of adults in the U.S. say they have felt confused as a result of changes to public health officials’ recommendations on how to slow the spread of the coronavirus.⁹ In addition to confusing patients, negative consequences of health misinformation include misallocation of health resources, fraud, increased reliance on unreliable cures, a negative impact on mental health, and an increased hesitancy to seek medical care.

CAN MISINFORMATION BE REGULATED?

If misinformation is a dangerous phenomenon, as many have suggested, can anything be done to control its flow? During COVID, officials from the federal government, many states, and healthcare and professional organizations promulgated regulations and policies aimed at limiting or promoting health information as will be described below. Some of these approaches have threatened to impose sanctions against practitioners who have disseminated erroneous or misleading information.

However, the suppression of information can face constitutional challenges.¹² Healthcare professionals, like all Americans, have a right to speech that is free of government restrictions even if the content is false.¹³

Justice Thurgood Marshall wrote in a Supreme Court decision in 1972, “…the First Amendment means that government has no power to restrict expression because of its message, its ideas, its subject matter, or its content.”¹⁴ The rights enumerated in the First Amendment protect individual against government infringement on their expression, but do not protect them from other individuals, businesses, or private organizations.¹⁵ Healthcare professionals can be disciplined by professional licensing boards and health departments for certain actions, but these organizations are governmental bodies (termed state actors in constitutional law) and they, along with public hospitals and universities, are prohibited from infringing on free speech.¹⁵

A content-based restriction “discriminates against speech based on the substance of what it communicates” and receives the greatest protection from any government-imposed restrictions.¹⁶ Content-based restrictions are presumptively unconstitutional and can only be applied if the state shows that the prohibition is the least restrictive means of achieving a compelling state interest such as the protection of public health and safety.¹⁶ (Compelling means essential or necessary rather than a matter of choice, preference, or discretion.¹⁶) The Supreme Court recognizes that certain narrow categories of expression, such as obscenity, child pornography, true threats, and incitement to imminent lawless action, can be barred because of their harmful content.¹⁶ Learners who are interested in learning more about how the courts scrutinize speech can find excellent information here: https://crsreports.congress.gov/product/pdf/R/R47986

Commercial speech, on the other hand, does not receive as much protection as content speech. Commercial speech applies when there is some form of transaction and includes commercial advertising and solicitations.^12,16 Historically, commercial speech did not receive any First Amendment protection, but an important 1976 Supreme Court decision involving pharmacies extended protection to commercial speech.¹⁶ The case, Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, challenged a state law that made it illegal for pharmacies to advertise drug prices. The Court reasoned that the First Amendment not only granted the speaker the right to speak, it also granted the listener the right to receive information. Commercial speech receives some protection because it serves the important societal interests of providing information to consumers and promoting the economic interests of the speaker.¹² In the case cited, consumers had a right to receive lawful information about drug prices.¹⁶ This narrow exception to free speech could apply in cases where a healthcare practitioner monetizes health misinformation.¹²

Commercial speech can be restricted if it is false, misleading, or proposes an illegal transaction since consumers must be able to make informed decisions.¹² Unlike political speech, where it may be difficult to ascertain what is truthful, courts recognize that commercial advertising is more objective and more readily subject to determination of its truthfulness.¹⁶

Courts have also traditionally recognized a third form of speech, professional speech, which is “uttered in the course of professional practice” as distinct from “speech . . . uttered by a professional.”¹⁷ This form of speech could also be restricted. Some courts have ruled that healthcare practitioners are entitled to less stringent First Amendment protection when providing professional advice to individual patients than when speaking to a larger audience about public issues.¹³

However, a 2018 Supreme Court decision overturned the prior recognition of professional speech as a separate category that would receive lesser First Amendment protection.¹² The Court’s decision stated that “speech is not unprotected merely because it is uttered by 'professionals.’” Consequently, speech expressed by professionals receives complete protection unless it falls under the commercial exception.

There are also practical concerns that sanctioning health professionals for questioning accepted medical standards when they feel they are inaccurate or misguided may stifle advances in practice.¹³ This is especially troublesome during a public health crisis when guidance from public health officials evolves as circumstances and knowledge unfold. The many examples of shifting public health recommendations during the COVID pandemic underscore this concern.¹⁸ Generally, healthcare providers have greater latitude when speaking on medical matters to the general public, such as on social media, than they do when providing medical advice to a specific patient.¹⁹

While constitutional protection is available to healthcare providers when sharing their view on medical matters, other legal situations can impact speech.¹⁹ An employment contract can restrict how much leeway a healthcare provider has, and tort law (malpractice claims) may provide penalties for improper medical advice, especially in the context of informed consent.^15,19

DISCIPLINING HEALTHCARE PROVIDERS FOR MISINFORMATION

Professional licensing boards provide oversight to ensure that rules governing the profession are followed.¹³ The structure and authority of medical and pharmacy boards vary from state to state.¹³ Each state has Practice Acts that prohibit licensed healthcare practitioners from engaging in “unprofessional conduct,” although the definition of unprofessional conduct may vary from state to state. Unprofessional conduct is the most common reason for disciplinary action against healthcare personnel.¹³ States have applied standards of professional conduct when trying to sanction healthcare personnel for misinformation (see below).

It should be apparent that when attempting to sanction a healthcare provider for misinformation, state regulatory agencies must walk a fine line. During COVID, a number of healthcare organizations endorsed revocation of the licenses and certifications of physicians who disseminated harmful health misinformation such as rejection of widely accepted preventive measures and endorsement of unproven treatments. The organizations included the Federation of State Medical Boards (FSMB) and professional certification boards such as the American Boards of Family Medicine (ABFM), Internal Medicine (ABIM), and Pediatrics (ABP).¹³

The FSMB took note of the “dramatic increase in the dissemination of COVID-19 vaccine misinformation and disinformation by physicians and other healthcare professionals on social media platforms, online and in the media” and issued a warning to physicians that that they risk suspension or revocation of their medical licenses by state medical boards if they generate and spread COVID-19 vaccine misinformation or disinformation.²⁰

The FSMB commented, “Due to their specialized knowledge and training, licensed physicians possess a high degree of public trust and therefore have a powerful platform in society, whether they recognize it or not. They also have an ethical and professional responsibility to practice medicine in the best interests of their patients and must share information that is factual, scientifically grounded and consensus-driven for the betterment of public health.” Although the statement focused on vaccination, it could apply to all health information and spreading inaccurate information undermines that responsibility and “threatens to further erode public trust in the medical profession and puts all patients at risk.”²⁰ Of course, the same comments would apply to pharmacists and other health professionals.

State medical boards have traditionally brought disciplinary actions against physicians for making false or misleading statements in situations such as serving as an expert witness in malpractice cases.²¹ Some state laws explicitly authorize disciplinary action against physicians who make false, deceptive, or misleading statements to the public. In most cases, these statutes apply to statements made in connection with advertising, especially when solicitating patients. (See distinction between content-based and commercial speech above.) However, some are worded broadly enough to cover other forms of misrepresentation.^13,21 For example, Minnesota authorizes disciplinary action against physicians who engage in “conduct likely to deceive or defraud the public.”²¹

It is not clear how often healthcare professionals are sanctioned for spreading misinformation, but it appears to be infrequent.²² The president of the FSMB has pointed out that medical license renewals are designed to be simple for applicants and it is usually an automatic procedural step. He added that medical boards do not have the capacity to review the large number of renewals that occur each year.²²

The license suspension process is long and slow with procedural barriers. Investigations will ordinarily begin only in response to a complaint, rather than being initiated by the board itself.²³ Licensing boards are primarily concerned with medical malpractice, patient abuse, and illegal activity, so misinformation takes a relatively low priority.²³ Moreover, both non-renewals and suspensions require due process.²² In addition, it can be difficult to evaluate whether a comment is outside the range of scientific and medical consensus and boards are reluctant to take action on a “fringe” opinion.²³ Investigations can take months or years to complete and many proceedings are conducted in private.²⁴ In many states the legal framework for discipline, which was developed in the 20^th century, may narrowly apply to actions or speech related directly to patients under the physician’s care and not to broader circumstances like social media.²⁵ Moreover, boards face daunting legal and policy obstacles if they try to take action (see below).^25,26 Political opposition from legislators in some states can also impede a board’s actions (see below).²⁵

The arguments for disciplinary proceedings by licensing boards usually emphasize the potential harm to public health.¹³ However, this may be insufficient to achieve constitutionality in most cases where it would be necessary to apply the “least restrictive means” test mentioned above.¹³ A state can instead mitigate the harm by disseminating factually accurate messages, especially in instances where the commercial speech exception would not apply.¹³

PAUSE AND PONDER: Is a state licensing board the best party to try to dissuade healthcare practitioners from issuing information of questionable validity?

Professional credentialing boards (private organizations providing certification) can also take steps to minimize misinformation. For example, consider a pharmacist who works in a large health system and has a specialized position running a hypertension clinic; she has been credentialed to prescribe medication and adjust dosing. The terms of her credentialing may restrict the type and quality of the information she can provide to patients and the credentialing board can retract her credentials if she begins to tell patients that ACE inhibitors are terrible antihypertensives. A joint statement from the ABFM, ABIM, and ABP declared that providing misinformation about the COVID-19 vaccine contradicts physicians' ethical and professional responsibilities and warned physicians that such conduct may prompt a Board to take action that could put their certification at risk.²⁸ (Credentialing boards as non-state actors have more latitude to impose penalties.)

STATE ACTIONS AND PUSHBACK

Concerns over misinformation during the pandemic prompted various health related organizations to take steps. Boards in at least a dozen states have issued sanctions against physicians for spreading dubious information.²⁴

While private professional organizations can impose loss of credentialing, state licensing boards can levy more serious sanctions such as loss of licensure or fines. Recent Board actions have generated a number of legal skirmishes. In addition to state regulatory bodies like licensing boards, state legislatures have acted directly to address misinformation. Different states have taken different – even opposite – approaches to this issue.

California

In 2022, the California legislature passed a bill stating that “the dissemination of misinformation or disinformation related to COVID-19 by physicians and surgeons constitutes unprofessional conduct.”²⁸ The types of false or misleading information that could lead to disciplinary action include communication about the nature and risks of the COVID-19 virus; its prevention and treatment; and the development, safety, and effectiveness of COVID-19 vaccines. False statements regarding prevention and treatment “would presumably include the promotion of treatments and therapies that have no proven effectiveness against the virus.” The bill’s proponents expressed the view that “providing patients with accurate, science-based information on the pandemic and COVID-19 vaccinations is imperative to protecting public health.” They also said that the bill was necessary because “licensed physicians ... possess a high degree of public trust and therefore must be held accountable for the information they spread.”²⁸ By passing this legislation, the law continues, “California will show its unwavering support for a scientifically informed populous to protect ourselves from COVID-19.”²⁸

PAUSE AND PONDER: Should laws such as those discussed above include other healthcare professionals, such as pharmacists, instead of focusing only on physicians?

Under the statute, the misinformation or disinformation must be conveyed “[by] the licensee to a patient under the licensee's care in the form of treatment or advice.”²⁸ It excludes speech outside of a direct physician-relationship such as social media postings.²⁹ California Governor Newsom also indicated that he is “confident that discussing emerging ideas or treatments including the subsequent risks and benefits does not constitute misinformation or disinformation under this bill's criteria."²⁹

The bill’s original intent was an effort to grant California’s Medical Board the power to discipline providers who were found to have conveyed misinformation about COVID vaccines and treatments. The proposed bill included statements they might make on social media or in other public forums such as public protests. It was narrowed, however, to apply only to conversations between a provider and a patient in clinical settings when the practitioner made statements that were "contradicted by contemporary scientific consensus contrary to the standard of care."³⁰ Opponents said the statute was overly broad and that information considered scientific consensus about the rapidly-mutating virus could change daily.³⁰ They also argued that providers had the right to express their opinions in clinical settings.³⁰

Two different lawsuits were filed seeking an injunction against enforcing the law and the judges hearing the cases reached different conclusions.³¹ In one case, the judge declined to grant the injunction.³¹

In the other, filed in a different California judicial district, a group of physicians licensed in California were joined by organizations representing the interests of doctors and patients. They sued the State alleging that the above statute was in breach of their First and Fourteenth Amendments rights (i.e., free speech and equal protection rights).³² The physicians had provided advice and treatments contrary to public health recommendations (universal masking or vaccines) and intended to continue to do so, claiming it was consistent with the standard of care.^32,33 They also claimed that the law’s definition of misinformation as false information that is “contradicted by contemporary scientific consensus” would suppress the ability of physicians to advise patients about the pros and cons of alternative COVID-19 treatment and practices.^32,33

The court in this case granted a temporary injunction, ruling that the law’s definitions of misinformation and the uncertainty about its enforcement were “unconstitutionally vague”³² The Court noted that a phrase defining the unlawful conduct, as contradicting “contemporary scientific consensus,” lacked any established meaning within the medical community and was not clarified further in the statute.³² They went on to say that it “fails to provide sufficiently objective standards to focus the statute’s reach.” The judge found this particularly problematic in the context of the pandemic since scientific understanding of the virus had repeatedly changed, negating a true consensus.³²

He went on to say that the law leaves many questions unanswered, such as who determines whether a consensus exists? Moreover, the judge ruled that the term “scientific consensus” is so ill-defined that the physicians would be “unable to determine if their intended conduct contradicts the scientific consensus, and accordingly ‘what is prohibited by the law.’”

The conflicting decisions necessitated a resolution (since the law could not be simultaneously upheld and enjoined). The first case was appealed, but the state repealed the law before the court could rule.³⁴ Following the court’s decision granting the injunction, the state rescinded the law about a year after it was signed.^30,31

Missouri

Missouri also enacted statutes dealing with the dissemination of COVID-related health information, but their approach was quite different from California. A law passed in 2022 prohibits the state boards overseeing medicine and pharmacy from disciplining a registered practitioner for “lawfully” prescribing or dispensing ivermectin or hydroxychloroquine for human use.³⁵ In other words, the prescribing or promotion of these drugs could not be used as a basis for establishing unprofessional conduct and sanctioning a healthcare practitioner.

A second part of the law prohibits pharmacists from contacting the prescribing a physician or the patient to dispute the efficacy of ivermectin or hydroxychloroquine unless the physician or patient inquires of the pharmacist about the drug’s efficacy.³⁵ In other words, a pharmacist would be prohibited from expressing legitimate concern about questionable treatments.³⁶ (The Missouri Pharmacy Association issued a clarification that pharmacies are not required to dispense nor stock the drugs, nor does it prevent a pharmacist from counseling a patient who should not take these drugs due to certain health conditions or interactions.³⁶)

A sponsor of the bill indicated that these actions were necessary because “certain pharmacists wanted to begin acting like physicians and denying the filling of the prescriptions. This re-establishes the professional equilibrium between doctors and pharmacists.”³⁷ No doubt most pharmacists are grateful that the equilibrium has been reestablished.

A pharmacist also challenged this law on First Amendment grounds. The pharmacist’s suit alleged that “all pharmacists in Missouri, now face the impossible—and constitutionally impermissible—conundrum of deciding whether to endanger their livelihood when choosing whether to speak in a manner that is both vital to their professional duties to patients and protected by the First Amendment.”³⁸ The pharmacist believed that it is a matter of legitimate professional ethics to contact a patient or prescriber to dispute a medication’s efficacy.

The court granted an injunction against implementation of the new law stating that the relevant section quoted above “infringes the free speech rights of Plaintiff and other Missouri-licensed pharmacists by threatening to impose liability based on the viewpoint of their speech.”³⁸ The court pointed out that the regulation “does not prohibit pharmacists from initiating contact to tout, endorse, or acclaim the drugs, thus it is taking sides in a politically charged debate about the drugs efficacy."³⁸ In other words, it was a content-based restriction of speech (see above) and therefore was an impermissible infringement of the First Amendment.

The Board replied that the statute was constitutional because it regulated conduct and not speech.³⁸ Unpersuaded by this argument, the court noted that the statute does not prohibit initiating contact with patients or prescribers which would be a permissible regulation of conduct. Instead, it prohibits contact only if the pharmacist wishes to "dispute the efficacy of ivermectin tablets or hydroxychloroquine sulfate tablets for human use.” The court also said that this interpretation is “consistent with the legislature's apparent purpose in enacting (the law): to insulate ivermectin or hydroxychloroquine from criticism.”³⁸

Elsewhere Around the U.S.

In other states, attempts by medical boards to restrict dissemination of health information that deviates from mainstream medicine have faced backlash from state legislatures. Dozens of state legislatures (e.g., North Dakota) have introduced or passed measures that would prevent a regulatory agency from punishing medical providers who promote COVID-19 misinformation or unproven treatments.^15,39

A particularly contentious dispute arose in Tennessee between the state licensing board and the state legislature. The Board of Medical Examiners unanimously declared that physicians spreading false information about COVID would put their license in jeopardy and the board posted the new policy on its website.⁴⁰ Soon afterwards, state legislators charged that the board had overstepped its authority and demanded that the statement be deleted from the state’s website. The state threatened to disband the board.^39,40

Many of the same Tennessee legislators had previously threatened to defund the Health Department when it promoted COVID vaccines to teens and introduced a bill that would have prevented the board from disciplining physicians for administering any treatment for COVID-19, even if it is not recommended by the Department of Health nor the FDA.³⁹ Another proposed bill would have prevented pharmacists from interfering with prescriptions to treat COVID.

Despite the threats, the Tennessee board voted to retain the misinformation policy with a tweaking of the definition of misinformation.⁴¹

A similar situation arose in Washington state. Four physicians threatened with disciplinary action by the state Medical Commission for misinformation challenged the commission's policy statement. They claimed that the commission did not follow their standard procedures in implementing the policy and that the position statement infringed their constitutional right to free speech.⁴² The physicians faced charges over their alleged care for COVID patients with unproven treatments and "false and misleading" statements regarding the pandemic and vaccination. The physicians maintained that the distinction between them and “other medical professional[s] who were not investigated and charged under the Statement is that plaintiffs dissented politically, scientifically and medically from health officials on various matters related to COVID.”⁴³ The physicians were charged with negligent care; one physician allegedly “failed to discuss alternative treatments” (monoclonal antibodies) with an elderly, unvaccinated patient with a COVID-19 infection who later died.⁴³

FDA Lawsuit

On a broader scale, the controversy over misinformation has even touched the FDA. In 2024, a lawsuit was brought against the FDA’s messaging with potentially very significant consequences. Three physicians in Texas who prescribed ivermectin to thousands of their patients for COVID initiated the suit.⁴⁴ They objected to the FDA’s public advisory and social media posts (“You are not a horse,” a post that is no longer available) warning patients not to use the drug. (See image here: https://www.pharmamanufacturing.com/compliance/regulatory-guidance/news/11291402/you-are-not-a-cow-fda-warns-public).⁴⁵ The physicians claimed that the messages exceeded the FDA’s authority and encroached on the practice of medicine.⁴⁴ The physicians alleged that the posts interfered with their “ability to exercise professional medical judgment in practicing medicine” and harmed their reputations.

The FDA claimed sovereign immunity (a legal doctrine that the government cannot be sued without its consent) in its defense.⁴⁶

The District Court (first level) judge hearing the case dismissed it, ruling that sovereign immunity protects the FDA.⁴⁶ The court also noted that Congress charged the FDA “with protecting public health and ensuring that regulated medical products are safe and effective” and that “FDA has the authority, generally, to make public statements in-line with these purposes.”⁴⁶

The physicians appealed, and the appellate judge reversed the decision, finding, often in very colorful language, that the FDA did exceed its legal authority.⁴⁶ The judge stated that no legal basis allows the FDA to issue recommendations or give medical advice. He wrote that the “FDA is not a physician. It has authority to inform, announce, and apprise—but not to endorse, denounce, or advise.”⁴⁶

The FDA argued that it has the authority to communicate information to the public and that the posts are purely informational and not imperative. The court, however, disagreed, finding that the posts contained syntax that directed patients to take action such as “Stop it with the #ivermectin.”⁴⁶ The court also chided the FDA for failing to mention that there is also a human version of ivermectin which was being used off-label to treat the coronavirus.⁴⁶

The FDA responded to the decision by agreeing to retire the consumer update entitled "Why You Should Not Use Ivermectin to Treat or Prevent COVID-19" and to delete various related social media posts.⁴⁷ The FDA issued a statement stating that "the agency has chosen to resolve this lawsuit rather than continuing to litigate over statements that are between two and nearly four years old" and that it “stands by its authority to communicate with the public regarding the products it regulates."⁴⁷ Furthermore, the agency indicated that it “has not changed its position that currently available clinical trial data do not demonstrate that ivermectin is effective against COVID-19” and reiterated that it “has not authorized or approved ivermectin for use in preventing or treating COVID-19."⁴⁷

While this might appear to be a minor dispute involving the agency and aggrieved prescribers, there are fears that it could have far-reaching implications. There is a concern that the FDA, and possibly other consumer-related regulatory agencies, may need to reevaluate all their communications to the public to ensure that they comply with the decision.⁴⁸ This would obviously limit the agency’s role as a public health educator. It could also disrupt the FDA’s ability to limit a manufacturer’s promotion of off label drug use.⁴⁸ In addition, the physicians’ claim that they suffered harm as a result of the FDA’s actions could lead to more claims against regulatory agencies for damages.⁴⁸ On the other hand, there is a consideration that the ruling could be challenged since it may be at odds with the constitutional principle of government speech in which the government can itself be a speaker and is not required to be neutral when expressing an opinion.⁴⁸

PAUSE AND PONDER: What should the FDA’s role be in discouraging misinformation?

SUMMARY AND FINAL COMMENTS

Misinformation about health matters became more troublesome during the COVID pandemic, raising concerns that this has had negative consequences for society and public health. Many professional and governmental organizations have expressed apprehension about the influence of health misinformation and have sought to limit its spread by sanctioning healthcare professionals. This has been met with legal challenges by the affected healthcare providers centering around First Amendment protection of speech. At the same time, legislators in many states have tried to suppress these efforts and limit the ability of licensing boards to discipline healthcare providers for their promotion of remedies outside of mainstream medicine. Some legislative efforts have also tried to restrict the ability of healthcare providers, including pharmacists, to express concerns about unproven treatments. Recently, messaging by the FDA has also been challenged with potentially far-reaching consequences. It is important for pharmacists to be aware of the positions taken by governmental agencies and legislators in their state and to respond accordingly.

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