Clinical Context

Amphetamines and methylphenidate are central nervous system (CNS) stimulants used medically for 85 years. Their complex mechanisms of action are incompletely determined but include increased dopamine and norepinephrine release.

Medical indications for stimulants over the course of past decades include nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and attention deficit hyperactivity disorder (ADHD). In the US, amphetamines, methylphenidate, opioids, and barbiturates are Schedule II controlled substances because of risks for addiction and nonmedical use.

Study Synopsis and Perspective

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 9.1 million US adults during 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, more than 45% combined these agents with 1 or more additional CNS drugs and almost 25% were simultaneously using 2 or more additional CNS-active drugs.

Close to half of the stimulant users were receiving an antidepressant, whereas 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. Similar to opioids and barbiturates, they are considered “dangerous” and are classified as Schedule II controlled substances because of their high potential for abuse.

Over the course of 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 that 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 Dr Moore, explores how these stimulants are being used.

For the study, data were extracted from the Market-Scan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19 to 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 1 additional CNS-active drug. “Combination-3” therapy was defined as the addition of at least 2 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 receiving 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 receiving stimulants, 45.5% combined the use of at least 1 additional CNS-active drug for a median of 213 (IQR, 126-301) treatment days, and 24.3% used at least 2 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.

“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,” Dr 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 a high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases,” the authors 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 does not include people who are not covered by commercial insurance.

Moreover, the MarketScan data set included up to 4 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

Dr Olfson, who is a research psychiatrist at the New York State Psychiatric Institute and was not involved with the study, observed that 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 nonelderly, 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 Dr 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. Dr Moore has disclosed no relevant financial relationships. Coauthor G. Caleb Alexander, MD, is past chair and a current member of the Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; is a cofounding 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. Dr Olfson has disclosed no relevant financial relationships.

BMJ Open. Published online April 24, 2023.^[1]

Clinical Implications

• Nearly half of adults using Schedule II stimulants were simultaneously exposed to at least 1 other CNS-active drug.
• These multidrug combinations have no approved indications and limited clinical trial testing and scientific evidence regarding risks and benefits.
• Implications for the Health Care Team: Clinicians should be aware of the prescribing cascade that leads to the addition of multiple drugs and the challenge when discontinuing 2 or more drugs with opposing therapeutic and withdrawal effects.

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