Widespread Prescribing of Stimulants With Other CNS Meds

Batya Swift Yasgur, MA, LSW

May 02, 2023

A large proportion of US adults who are prescribed Schedule II stimulants are simultaneously receiving other CNS agents including benzodiazepines, opioids, and antidepressants — a potentially dangerous practice.

Investigators analyzed prescription drug claims for over 9.1 million US adults over a 1-year period and found that 276,223 (3%) had used a Schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with one or more additional CNS drugs and almost 25% were simultaneously using two or more additional CNS-active drugs.

Close to half of the stimulant users were taking an antidepressant, while close to one third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one fifth received opioid prescriptions.

The widespread, often off-label use of these stimulants, in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, "reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for ADHD, but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown," study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, Maryland, told Medscape Medical News.

The study was published online April 24 in BMJ Open.

"Dangerous" Substances

Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they're considered "dangerous" and classified as Schedule II Controlled Substances because of their high potential for abuse.

Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.

Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Moore, explores how these stimulants are being used.

For the study, data was extracted from the Market-Scan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from October 1, 2019 to December 31, 2020.

The primary outcome consisted of an outpatient prescription claim, service date, and days' supply for the CNS-active drugs.

The researchers defined "combination-2" therapy as 60 or more days of combination treatment with a Schedule II stimulant and at least one additional CNS-active drug. "Combination-3" therapy was defined as the addition of at least two additional CNS-active drugs.

The researchers used service date and days' supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020.

CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.

Prescribing Cascade

Of the total number of adults enrolled, 3% (n = 276,223) were taking Schedule II stimulants during 2020, with a median of 8 (interquartile range 4-11) prescriptions. These drugs provided 227 (IQR 110-322) treatment days of exposure.

Among those taking stimulants 45.5% combined the use of at least one additional CNS-active drug for a median of 213 (IQR 126-301) treatment days; and 24.3% used at least two additional CNS-active drugs for a median of 182 (IQR 108-276) days.

Table. Other CNS-active drugs by drug class among those exposed to Schedule II stimulants in 2020.

Medication class % of stimulant users
Antidepressant 47.6%
Anxiolytic/sedative/hypnotic 30.8%
Opioids (Schedule II) 15.5%
Anticonvulsant 13.8%
Antipsychotic 8.2%
CNS (other) 5.3%
Opioids (other) 4.1%
Stimulant (other) 1.6%


"Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix," Moore said.

He cautioned that this "leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects."

These new findings, the investigators note, "add new public health concerns to those raised by our previous study...this more-detailed profile reveals several new patterns."

Most patients become "long-term users" once treatment has started, with 75% continuing for a 1-year period.

"This underscores the possible risks of non-medical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases," they write.

They note that the data "do not indicate which intervention may have come first — a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs."

Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it "may not represent all commercially insured adults" and it doesn't include people who aren't covered by commercial insurance.

Moreover, the MarketScan dataset included up to four diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.

"Since many providers will not accept a drug claim for a Schedule II stimulant without an on-label diagnosis of ADHD," the authors suspect that "large numbers of this diagnosis were present."

Complex Prescribing Regimens

Commenting for Medscape Medical News, Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York City, said the report "highlights the pharmacological complexity of adults who are treated with stimulants."

Olfson, who is a research psychiatrist at the New York State Psychiatric Institute and was not involved with the study, observed there is "evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults."

However, he added, "this indication is unlikely to fully explain the high proportion of non-elderly, stimulant-treated adults who also receive antidepressants."

These new findings "call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety," said Olfson.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Moore declares no relevant financial relationships. Co-author G. Caleb Alexander, MD, is past chair and a current member of FDA's Peripheral and Central Nervous System Advisory Committee; is a co-founding principal and equity holder in Monument Analytics, a healthcare consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation, for whom he has served as a paid expert witness; and is a past member of OptumRx's National P&T Committee. Olfson declares no relevant financial relationships.

BMJ Open. Published online April 24, 2023. Full text

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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