Changes in medical use of central nervous system stimulants among US adults, 2013 and 2018: a cross-sectional study

Abstract

Objective

To assess the 5-year changes in the adult medical use of central nervous system (CNS) stimulants with higher risk of dependence and evaluate the population characteristics of users and their medical and/or neurological conditions.

Design

Cross-sectional study.

Setting

Annual US Medical Expenditure Panel Survey, a stratified random sample of approximately 30 000 persons designed to produce national population estimates. It focuses on reported medical spending, medical services used, health status and prescription medications.

Participants

Adults age 19 years and older who reported obtaining one or more prescriptions for amphetamine or methylphenidate products during two survey years, 2013 and 2018.

Main outcomes measures

Prescriptions obtained, the specific stimulant product and annual treatment days of drug supplied.

Results

In 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported prescriptions for CNS stimulants, having filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions with a mean of 226 (95% CI 210 to 242) days’ supply. Compared with 2013, the estimated number of adults reporting using CNS stimulants in 2018 increased by 1.8 million (95% CI 1.0 million to 2.7 million) or 79.8%. Most 2018 adult stimulant users reported taking psychoactive medication for one or more mental, behavioural or neurodevelopment disorders. Overall, 77.8% (95% CI 72.6% to 83.0%) reported some medication for adult attention deficit disorder, 26.8% (95% CI 22.2% to 31.5%) took medication for anxiety, 25.1% (95% CI 19.9% to 30.3%) for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug treatment for other mental or neurological disorders. Adult CNS stimulant use was higher in females, in younger age cohorts and among individuals of white race/ethnicity.

Conclusions

Adult medical use of prescription stimulants increased markedly in 5 years and occurred in a population often reporting multiple mental or neurological disorders. Further action is needed to understand and manage this new resurgence in drugs with high risks of dependence.

Strengths and limitations of this study.

• This analysis of adult use of prescription amphetamine and methylphenidate stimulants is based on the largest publicly available annual US health survey conducted annually since 1996.

• While the utilisation of these stimulant drug products in 2013 and 2018 was self-reported in an annual household survey, the prescription detail was confirmed in pharmacy records.

• The annual, federally funded survey was designed to support health policy analysis; its multistage probability design supports population estimates and CIs for the entire US population.

• With an overall survey random sample of approximately 30 000 households and 325 000 dispensed prescriptions for each year, the number of cases indicating the study drug products was modest.

• Given stimulant drugs with a higher risk of psychological or physical dependence, as well as risks of non-medical use, the self-reporting feature of this survey could result in underestimating actual exposure among adults.

Introduction

The central nervous system (CNS) stimulants amphetamine and methylphenidate are among the oldest synthetic psychoactive medications still in widespread clinical use. The amphetamine product Benzedrine was first marketed in 1933 for nasal congestion and in 1937 for depression and narcolepsy¹; in 1954, the US Food and Drug Administration (FDA) approved a methylphenidate product (Ritalin), which was marketed for depression, senile behaviour, lethargy and narcolepsy.²

Amphetamine and methylphenidate are potent and structurally related sympathomimetic amines with therapeutic mechanisms that remain unclear but stimulate the release of dopamine and norepinephrine primarily through inhibition of neuronal reuptake.³ Currently, a large number of amphetamine products are licenced based on mixtures of various salts (saccharate, sulfate and aspartate), specific enantiomers (d-), extended release formulations and a prodrug. Methylphenidate has fewer chemical variants but is available in immediate and extended release formulations, d-enantiomer salt mixtures and a transdermal patch. Multiple generics and brand name variants are available for both stimulants. Approved and off-label uses of these two CNS stimulants have evolved over the many decades. Medical use for depression and weight loss declined in the 1950s and 1960s, and these indications were repealed over concern about growing evidence of misuse and questions about effectiveness.¹ However, beginning in 1961, use in children expanded with FDA approval of indications for treating behavioural problems and later for attention deficit hyperactivity disorder (ADHD).⁴ For many years, new formulations were approved based on studies of ADHD in children. Starting in 2004, the FDA extended the ADHD indication to adults for some branded stimulants (Adderall XR, Concerta, Vyvanse) and in 2015 approved a binge eating indication for lisdexamfetamine (Vyvanse).^5–7 Throughout the decades since initial marketing, the two stimulant products were approved for narcolepsy, and during that time, off-label use was observed among persons using them to increase alertness or seeking to achieve cognitive enhancement.⁸

Amphetamine and methylphenidate have been long restricted globally because of addiction risks including a United Nations Convention on Psychotropic Substances and specific legal controls in many countries, including the UK, Canada and Australia.^9–12 In the USA, these stimulants are classified as Schedule II Controlled Substances, those declared to have ‘a high potential for abuse which may lead to severe psychological or physical dependence’.¹³ Other major Schedule II drugs include higher potency opioids and the barbiturates. Restrictions for this highest risk class of licit psychoactive drugs include a Drug Enforcement Administration licence to prescribe, limitations on prescribed refills, monitoring at the state and federal levels and secure pharmacy storage measures to prevent theft and diversion. In addition to risks of misuse and dependence, other adverse events associated with these stimulants include serious cardiovascular reactions, seizures, tics, tremors, aggression, manic symptoms and psychosis.^{5–7 14} Given that the increased use of prescription opioids continued for many years before declining in response to numerous public health initiatives, we examined the most recent trends in exposure to the other widely used group of Schedule II drugs: the CNS stimulants amphetamine and methylphenidate.

Methods

We extracted the data for this study from the US Medical Expenditure Panel Survey (MEPS), a healthcare survey of individuals and households conducted annually since 1996 and published for research use by the Agency for Healthcare Research and Quality.¹⁵ To assess change over 5 years, this study analysed the 2013 and 2018 annual surveys. MEPS collects data from a nationally representative sample of approximately 30 000 persons each year, and its multistage probability design supports estimates and variance of the US population. The confidentiality of personal identifying information is protected by federal law and removed before survey data are released for public research use.¹⁶ These deidentified public use data are exempt from review by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board.

Identification of medications

Population estimates of exposure to prescription drugs in MEPS begin with the household survey questionnaire and are then expanded with more detailed information collected from respondents’ pharmacies.¹⁷ Each annual data release contains a prescribed medicines file with records for approximately 325 000 prescriptions and multiple fields identifying the drug prescription detail. We used the following algorithm to standardise medications: if the record contained a National Drug Code (NDC), we matched it to the ingredient name in the National Library of Medicine RxNorm database¹⁸; for prescription records without an NDC, we used the Multum Lexicon medication name, which is defined as the generic name most commonly used by physicians.¹⁷ Medication names provided by respondents that were vague or described a class of drugs (eg, stimulants and antidepressants) were excluded. The outpatient medications identified by survey respondents were then confirmed in pharmacy records, which also provided additional detail about each dispensed prescription for the survey year.¹⁹

For this study, we identified persons reporting any use of the following standardised generic medication names: amphetamine/dextroamphetamine, lisdexamfetamine, methylphenidate and dexmethylphenidate. Notably, lisdexamfetamine and dexmethylphenidate are newer brand name drugs without generics. Amphetamine/dextroamphetamine and methylphenidate describe multiple generic products. The objective of analysing the two newer brand name products separately was to measure any effects of marketing and promotion, as compared with generics. We excluded CNS stimulants that were not classified as Schedule II (eg, atomoxetine), or those with utilisation that was too infrequent to estimate in the MEPS data (prescription methamphetamine). The extent of each respondent’s exposure was measured by calculating the number of prescriptions filled in the survey year and the total annual days’ supply reported for these prescriptions. If the days’ supply was missing for a prescription, we imputed the days’ supply based on median days supply for that drug (eg, lisdexamfetamine) among respondents with non-missing values. For some analyses, we also combined the four products into these two groups: amphetamine and methylphenidate products.

This study population included all persons reporting that they were 19 years of age or older as last ascertained during the survey year. Other assessed population characteristics included sex, race/ethnicity, education and marital status. Among those reporting exposure to Schedule II CNS stimulants, we also analysed the mental health, neurological or developmental conditions for which respondents indicated one or more of the following: (1) they had the condition during the survey year; (2) they took a prescribed medication for the condition; and (3) they received medical treatment, defined as an office, outpatient, inpatient or emergency department visit. The mental health conditions analysed were identified by the following International Classification of Disease, 10th Revision (ICD-10) codes: ADHD (F90), major depression (F32), anxiety (F40 and F41) and other neurological or mental conditions (all other ICD-10 codes in the ‘F’ series). The mental health condition information in the ICD-10 coding format was not available for the year 2013, limiting this analysis to the 2018 survey year data.

Statistical analysis

We estimated the exposed adult population totals, percentages and 95% CIs using the MEPS multistage probability design characteristics for the entire US population in accordance with the survey statistical methods documentation.²⁰ Each survey observation included data on the sampling unit, the sampling stratum and the specific sample weight for each observation. Populations, variance and statistical significance within survey years were estimated using Taylor series linearisation. SEs and CIs were calculated based on the weighted estimates when available. A Z-test of two binomial proportions was used to compare the proportions across years. All analyses were performed using SAS V9.4 (SAS Institute) and were conducted from July to October 2020.

Public and patient involvement

The public/patients were not involved in the design, conduct or reporting of this study.

Results

Stimulant population characteristics

In 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported that they had filled one or more prescriptions for the CNS stimulants amphetamine or methylphenidate. Population characteristics are shown in table 1. Use of these prescription stimulants skewed towards the younger age cohorts, and the percentage reporting prescription use was highest among those age 19–24 years— 3.2% (95% CI 1.7% to 4.8%)—and lowest among those age 65–85 years—0.5% (95% CI 0.3% to 0.7%). Utilisation also varied substantially by race/ethnicity with 2.3% (95% CI 1.8% to 2.8%) of whites reporting use compared with 0.6% (95% CI 0.3% to 1.0%) of blacks, a nearly fourfold difference. CNS stimulant use was also higher in those with education beyond high school and among those never married compared with those currently or previously married.

Table 1.

Adult demographic characteristics and population estimates, 2013 and 2018

	2013 US adult population	Taking Schedule II CNS stimulants				2018 US adult population	Taking Schedule II CNS stimulants
		Number	95% CI		%		Number	95% CI		%
Sample size	25 999	187			0.7	22 592	312			1.4
Weighted total	237 542 474	2 296 473	1 793 935	2 799 011	1.0	248 422 599	4 128 752	3 414 679	4 842 825	1.7
Gender
Male	114 248 604	1 315 701	957 355	1 674 048	1.2	119 882 386	1 827 177	1 393 945	2 260 410	1.5
Female	123 293 870	980 772	706 623	1 254 920	0.8	128 540 213	2 301 574	1 882 252	2 720 897	1.8
Age group
19–24	26 118 821	578 917	349 554	808 281	2.2	24 075 889	772 502	400 828	1 144 176	3.2
25–44	81 793 471	1 033 683	724 965	1 342 401	1.3	86 681 356	1 914 712	1 514 676	2 314 747	2.2
45–64	83 167 154	581 227	387 805	774 649	0.7	83 002 693	1 166 798	930 809	1 402 788	1.4
65–85	46 463 029	102 646	22 645	182 647	0.2	54 662 660	274 739	160 564	388 915	0.5
Race/ethnicity
Hispanic	35 671 675	99 783	42 216	157 350	0.3	40 404 296	286 699	137 849	435 548	0.7
White	155 869 496	1 991 331	1 519 826	2 462 836	1.3	155 534 457	3 508 558	2 868 675	4 148 442	2.3
Black	27 243 504	85 026	34 260	135 791	0.3	29 399 571	188 157	88 320	287 995	0.6
Asian	13 016 744	12 152	0	26 575	0.1	15 222 103	4 702		13 994	0
Multiple/other	5 741 056	108 181	31 355	185 007	1.9	7 862 172	140 636	39 820	241 452	1.8
Education
Less than 12 years	31 831 465	152 491	41 377	263 604	0.5	29 281 941	205 801	91 374	320 228	0.7
High school	63 162 840	427 477	231 253	623 700	0.7	69 557 184	679 812	465 308	894 315	1
Some college	73 555 386	853 103	556 308	1 149 898	1.2	65 099 328	1 588 589	1 138 409	2 038 770	2.4
College (16 years)	41 972 988	497 804	312 628	682 980	1.2	50 233 073	1 037 728	777 809	1 297 646	2.1
> College	25 382 768	328 152	188 049	468 256	1.3	32 182 381	595 711	378 295	813 127	1.9
Marital status
Married	126 006 314	873 147	602 927	1 143 366	0.7	127 963 174	1 538 405	1 220 135	1 856 675	1.2
Widow/sep/divorced	47 913 352	296 835	143 947	449 723	0.6	51 490 812	723 526	502 261	944 790	1.4
Never married	62 532 999	1 126 492	790 959	1 462 024	1.8	68 963 284	1 866 821	1 370 429	2 363 213	2.7

CNS, central nervous system.

CNS stimulant medication use

In 2018, US adults filled an estimated 30.2 million prescriptions (95% CI 27.9 million to 32.4 million) for CNS stimulants. Medication detail is shown in table 2. These adults filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions during the survey year, which provided a mean of 226 (95% CI 210 to 242) days’ supply. Amphetamine products were more widely used among adults than methylphenidate products, accounting for 78.9% versus 21.1% of the 2018 prescription volume.

Table 2.

Adult reported prescriptions for Schedule II stimulants 2013 and 2018

	2013				2018
	Number	95% CI		%	Number	95% CI		%
Sample size	1247				2336
All schedule II stimulants (weighted)	15 412 693	13 927 848	16 897 539		30 150 428	27 929 702	32 371 154
Amphetamine products	10 859 022	9 461 363	12 256 680	70.5	23 803 206	21 847 712	25 758 700	78.9
Amphetamine/dextroamphetamine	8 628 463	7 321 851	9 935 075	56	19 173 869	17 229 361	21 118 377	63.6
Lisdexamfetamine	2 230 558	1 672 254	2 788 863	14.5	4 629 337	3 888 062	5 370 612	15.4
Methylphenidate products	4 553 672	3 796 140	5 311 204	29.5	6 347 222	4 984 163	7 710 281	21.1
Methylphenidate	4 303 540	3 561 713	5 045 367	27.9	5 886 552	4 346 483	7 426 621	19.5
Dexmethylphenidate	250 132	0	534 579	1.6	460 670	166 583	754 756	1.5
Prescriptions per patient (mean, 95% CI)	6.7	6.1	7.4		7.3	6.8	7.8
Annual days supply (mean, 95% CI)	208	187	229		226	210	242

Change in utilisation

Reported use of these CNS simulants increased during the 5 years from the 2013 to the 2018 annual MEPS survey. Survey-to-survey changes are shown in table 3. The estimated number of adults increased from 2.3 million (95% CI 1.8 million to 2.8 million) in 2013 to 4.1 million (95% CI 3.4 million to 4.8 million) in 2018. During that period, adult exposure increased by an estimated 1.8 million adults (t=4.35, p<0.01) or an increase of 79.8%. Examined by sex, the largest increase occurred among females, who accounted for 1.3 million of 1.8 million (72.1%) of the 5-year growth (difference: t=5.39, p<0.01). Male use increased by 0.5 million, a 38.9% nominal increase that was not statistically significant (t=1.86, p=0.063). Change in use by age was concentrated in two cohorts, age 25–44 years and age 45–64 years. Among those age 25–44 years, an additional 0.88 million (95% CI 0.39 million to 1.37 million) reported stimulant use from 2013 to 2018 (t=3.55, p<0.01) or an increase of 85.2%. Among those age 45–64 years, estimated stimulant use increased by 0.59 million (t=3.81, p<0.01) or 100.7%. Among those in the youngest age cohort, age 19–24 years, the initial rate of utilisation in 2013 was the highest of any age group (3.2%), but the increases were smaller, a nominal increase of 33.4% that was not statistically significant (t=0.91, p=0.365). Meanwhile, the total adult US population was estimated to increase during the 5-year period from 237.5 million to 248.4 million, an increase of 4.6%.

Table 3.

Changes in Schedule II CNS stimulant use, 2013 and 2018

	Persons, number who took CNS stimulants
	2013	2018	Difference	95% CI		T	P	Change t1–t2,(%)
All adults	2 296 473	4 128 752	1 832 279	1 006 626	2 657 932	4.35	<0.01	79.8
Gender
Male	1 315 701	1 827 177	511 476	- 28 416	1 051 368	1.86	0.063	38.9
Female	980 772	2 301 574	1 320 802	840 273	1 801 333	5.39	<0.01	134.7
Age group (years)
19–24	578 917	772 502	193 585	- 224 956	612 126	0.91	0.365	33.4
25–44	1 033 683	1 914 712	881 029	394 685	1 367 372	3.55	<0.01	85.2
45–64	581 227	1 166 798	585 571	284 399	886 745	3.81	<0.01	100.7
65–85	102 646	274 739	172 093	35 088	309 099	2.46	0.014	167.7

	Stimulant prescriptions, number dispensed
	2013	2018	Difference	95% CI			p	Change t1–t2 (%)
All schedule II stimulants	15 412 693	30 150 428	14 737 735	12 105 049	17 370 420	10.97	<0.01	95.6
Amphetamine products	10 859 022	23 803 206	12 944 184	10 518 473	15 369 896	10.46	<0.01	119.2
Methylphenidate products	4 553 672	6 347 222	1 793 550	244 341	3 342 759	2.27	0.023	39.4

CNS, central nervous system.

The growth in stimulant prescriptions was concentrated in the amphetamine products, which were estimated to increase 119.2% from 10.9 million in 2013 to 23.8 million in 2018 (t=10.46, p<0.01). Growth in use of methylphenidate products was slower, with an estimated 39.4% increase (t=2.27, p=0.023).

Medical conditions

Stimulant users frequently reported taking medications for a variety of mental, neurological and developmental conditions. The 2018 survey results are shown in table 4. Among those exposed to the stimulants, 77.8% (95% CI 72.6% TO 83.0%) indicated they took medication for ADHD, 26.8% (95% CI 22.2% to 31.5%) reported anxiety medication, 25.1% (95% CI 19.9% to 30.3%) said they had taken drugs for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug therapy for other mental or neurological conditions. As shown in table 4, similar percentages reported a medical visit for the reported condition and/or indicated a medical condition, regardless of whether it was treated with drugs or a medical visit. Overall, 40.6% (95% CI 34.9% to 46.3%) of those reporting stimulant use indicated they were taking medication for anxiety, depression or both.

Table 4.

Adult Schedule II stimulant users’ mental, neurological conditions, 2018

	Reported medication		Reported medical visit*		Reported condition
	%	95% CI	%	95% CI	%	95% CI
Mental, neurological condition
ADHD	77.8	72.6 to 83.0	79.3	73.3 to 85.4	79.3	73.3 to 85.4
Anxiety	26.8	22.2 to 31.5	31.2	26.3 to 36.2	31.2	26.3 to 36.2
Depression	25.1	19.9 to 30.3	28.3	22.8 to 33.8	28.3	22.8 to 33.8
Other mental	15.3	9.8 to 20.8	19.8	14.3 to 25.3	19.8	14.3 to 25.3
Anxiety and/or depression	40.6	34.9 to 46.3	45.0	39.3 to 50.8	45.0	39.3 to 50.8

*Medical visit=includes office, inpatient, outpatient or emergency department.

ADHD, attention deficit hyperactivity disorder.

Discussion

In this study, we have shown that US adult exposure to prescription CNS stimulants with risk of dependence is substantial—an estimated 4.1 million adults in 2018—and has grown by approximately 80% over 5 years. The total number of prescriptions dispensed grew even faster, with an increase of approximately 96%. Medication and treatment for depression, anxiety and other mental conditions were common. Those adults reporting stimulant use represented a population that was younger, had higher educational attainment and was more likely to be unmarried. While use remained more frequent in the youngest age cohort, the largest percentage increases occurred in adults age 25 years and older.

The most frequently reported disorder was ADHD. These data confirm, and extend to more recent years, results of previous studies indicating increasing diagnosis and drug treatment of adults for ADHD covering time periods from 1999 to 2016.^21–24 One study of adults with ADHD in a large integrated health system also reported high rates of comorbid depression and anxiety.²¹ Another study of ADHD diagnosis and treatment based on office visit data in an earlier 5-year period (2008–2009 to 2012–2013) reported a 36.4% increase.²⁴ Our analysis differs from these studies in that the primary focus was to assess the exposure to stimulant drugs for any medical purpose, given the varied off-label and on-label uses over many decades.

While we did not assess safety in this study, some patterns of use raise issues that warrant further investigation. Notably, given that amphetamine stimulants are reported to cause anxiety in 10%–50% of patients and methylphenidate in 10%–30% (p. 323),²⁵ we observed that anxiety was the second most frequently reported mental condition reported, accounting for 31.2% of exposed adults. Combination therapy with antidepressants also warrants further investigation given that many antidepressant drugs are associated not only with adverse effects of anxiety and insomnia, but also dullness and flat affect (p. 410).³ None of the major antidepressants are FDA approved for use in combination therapy with Schedule II stimulants.

Finally, the growing use of these stimulants should renew interest in updating, characterising and managing the risks of this drug class. There are three concerns warranting investigation. First, these data show that use of CNS stimulants is overwhelmingly in the long term, with a median of 226 days’ supply. Second, the skew towards use in younger age groups raises the question of whether or when those prescribed stimulants for ADHD in childhood or adolescence should be discontinued as they grow older. Third, while the estimates are not comparable, the major government survey of drug use and mental health for 2018²⁶ reported that the total number of adults estimated to make non-medical use of CNS stimulants was higher that our total of adults with self-reported medical use. Other studies indicate widespread use in hopes of achieving cognitive enhancement.⁸

This study also has limitations. Although MEPS is the largest publicly available survey providing data on the US use of prescription drugs, our population estimates are derived from two random samples of modest size. A source of potential bias was that utilisation was self-reported and might underestimate true exposure because of possible non-medical use, poor recollection or beginning therapy part way through the survey year. However, most self-reported medications were confirmed in pharmacy records and additional detail about each prescription collected from pharmacy records. While a validation study of this issue reported good agreement between self-reports and pharmacy records, the stimulant controlled substance drugs were not assessed in that study, and agreement could differ. During the period, the US adult population increased by 4.6%, which could contribute to increased use. While we could report the mental and neurological conditions such as ADHD and anxiety and whether medication was prescribed, we could not link these conditions to specific stimulant medications or combinations of medications. The intended medical purpose of various medications was further confounded because some widely used medications are indicated for multiple conditions (eg, paroxetine and sertraline are approved for both depression and social anxiety disorder) and because it is uncertain whether combinations were used intentionally in off-label combinations, or unintentionally.

Conclusions

Adult reporting medical use of those stimulants with the highest risk of misuse and dependence increased markedly in 5 years and occurred in a population often reporting multiple neurological or mental disorders. Given that the epidemic in use of prescription opioids continued for years before public health initiatives began to control use, understanding and managing this new resurgence in a class of drugs with a decades-long history of problems should be a public health priority. Physicians seeing patients who request prescriptions for these stimulants should assess with care the risks, benefits and medical need.

Data availability statement

Data are available in a public, open access repository. The data for this study are publicly available for research use from the US Agency for Healthcare Research and Quality. https://www.meps.ahrq.gov/mepsweb/

Ethics statements

Patient consent for publication

Not required.

Ethics approval

This study reports deidentified personal data protected by US federal law and published for unrestricted public research use; institutional review board approval is not required.