Is Age of Onset and Duration of Stimulant Therapy for ADHD Associated with Cocaine, Methamphetamine, and Prescription Stimulant Misuse?

Abstract

Background:

To assess whether age of onset and duration of stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) are associated with cocaine, methamphetamine, and prescription stimulant misuse during adolescence.

Methods:

Nationally representative samples of US 10^th and 12^th grade students (N=150,395) from the Monitoring the Future study were surveyed via self-administered questionnaires from sixteen annual surveys (2005–2020).

Results:

An estimated 8.2% of youth received stimulant therapy for ADHD during their lifetime (n=10,937). More than one in ten of all youth reported past-year prescription stimulant misuse (10.4%)—past-year cocaine (4.4%) and methamphetamine (2.0%) use were less prevalent. Youth who initiated early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years) did not have significantly increased adjusted odds of cocaine or methamphetamine use relative to population controls (ie, non-ADHD and unmedicated ADHD youth). Youth who initiated late stimulant therapy for ADHD (≥10 years old) and for short duration (<1 year) had significantly higher odds of past-year cocaine or prescription stimulant misuse in adolescence than those initiating early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years). Youth who initiated late stimulant therapy for ADHD (≥10 years) for short duration (<1 year) had significantly higher odds of past-year cocaine, methamphetamine, and prescription stimulant misuse versus population controls during adolescence. No differences in past-year cocaine, methamphetamine, and prescription stimulant misuse were found between individuals who only used non-stimulant therapy for ADHD relative to youth who initiated early stimulant therapy (≤9 years old) and for long duration (≥6 years).

Conclusions:

An inverse relationship was found between years of stimulant therapy and illicit and prescription stimulant misuse. Adolescents with later initiation and/or shorter duration of stimulant treatment for ADHD should be monitored for potential illicit and prescription stimulant misuse.

INTRODUCTION

The diagnosis of attention-deficit/hyperactivity disorder (ADHD) and prescribing of stimulant therapy for ADHD have increased significantly in the US.^1–3 Approximately 10% of US children and adolescents aged 4 to 17 have received an ADHD diagnosis (over 6 million children), and three-fourths of youth with a current ADHD diagnosis received medication therapy for ADHD.^4,5 While stimulant therapy for ADHD is highly effective when used appropriately and mitigates longer-term sequelae of ADHD,⁶ controversies continue to perplex the clinical and public health fields.^7,8

One growing concern is that stimulant therapy appears to be associated with an increased risk of illicit and prescription stimulant misuse.^9–15 The literature validates the potential for misuse of prescription stimulants; thus, it would be beneficial for prescribers to be able to identify specific patient characteristics or prescribing patterns that are associated with increased risk.¹⁶ Prescription stimulants have emerged as the leading class of controlled medications that are misused by US young adults.^17,18 Indeed, the number of young adults misusing stimulant medications without a legal prescription exceeds the number of young adults using prescription stimulants with a prescription.^17,19

Children with ADHD are at heightened risk for initiating substance use and developing substance use disorders (SUDs), including illicit/prescription stimulant misuse and stimulant use disorders.^7,15,20–24 There have been increases in stimulant-related adverse consequences, driven primarily by cocaine and methamphetamine, such as a ten-fold increase in US stimulant-related overdose deaths in the past decade.²⁵ While there is evidence that stimulant therapy for ADHD is not associated with an increase in the risk for overall SUD,⁶ especially for longer duration stimulant medication treatment,^26–28 it remains unclear how age of onset and duration of stimulant therapy for ADHD are associated more specifically with illicit stimulant and prescription stimulant misuse, especially in national samples. The concern that prescription stimulants may be associated with illicit drug use and prescription stimulant misuse stems in part from the pharmacological similarities between prescription stimulants and illicit stimulants,⁸ and a high prevalence of prescription stimulant misuse among those prescribed stimulant therapy in older adolescence and young adulthood.^12–14 Additionally, a Danish study found that older age of onset of stimulant treatment for ADHD was associated with higher risk of later substance use in a clinical sample, while early initiation was associated with lower risk.²⁹ Taken together, it is critical to examine whether clinically relevant associations exist between the onset and duration of prescription stimulants and the risk of illicit stimulant use. For example, at least one prospective longitudinal clinical study of 176 males ages 6–12 who were treated with methylphenidate (MPH) for ADHD showed that early age at initiation of MPH treatment did not increase the risk for lifetime SUD.³⁰ Indeed, there were no differences in lifetime SUD between ADHD youth with early onset of MPH therapy and non-ADHD youth.³⁰

Although clinical studies have examined stimulant therapy for ADHD and subsequent risk for SUD,^30–36 these studies suffer from limitations such as small homogeneous samples, non-random sampling, and lack of attention toward both non-stimulant and stimulant therapy for ADHD. The associations among age of onset and duration of stimulant therapy for ADHD, illicit stimulants (eg, cocaine, methamphetamine) and prescription stimulant misuse have yet to be examined in large probability-based samples of US children and adolescents. Addressing this gap is particularly important before young adulthood when individuals often become responsible for their medication regimen and illicit substance use escalates.¹⁸

The main objective of this multi-cohort US national study is to examine if early onset with longer duration prescription stimulant medication for ADHD is associated with lower or higher rates of cocaine, methamphetamine, and prescription stimulant misuse during late adolescence. Based on clinical and preliminary epidemiological evidence, we tested the following hypotheses:

• Hypothesis 1A: Among youth diagnosed with ADHD, earlier age of stimulant therapy initiation (≤9 years old) and longer duration of treatment (≥6 years) will be associated with lower risk of prescription stimulant misuse, cocaine use, and methamphetamine use during adolescence than those with later stimulant therapy initiation (≥10 years old) and shorter treatment duration (<1 year).

• Hypothesis 1B: Among youth diagnosed with ADHD, intermediate stimulant therapy duration (2–5 years) will be associated with lower risk of prescription stimulant misuse, cocaine use, and methamphetamine use during adolescence than later stimulant therapy initiation and shorter treatment duration; intermediate stimulant therapy duration, however, will be associated with higher risk of stimulant misuse outcomes than earlier age of stimulant therapy initiation and longer duration of treatment.

• Hypothesis 2: Rates of stimulant misuse will not differ significantly between population controls and youth diagnosed with ADHD who initiate stimulant therapy early (≤9 years old) and maintain treatment for at least 6 years.

• Hypothesis 3: Among youth diagnosed with ADHD, later stimulant therapy initiation (≥10 years old) and shorter treatment duration (<1 year) will be associated with significantly higher risk of prescription stimulant misuse, cocaine use, and methamphetamine use during adolescence than population controls.

METHODS

Study design

The Monitoring the Future (MTF) study surveys a cross-sectional, nationally representative sample of high school 10^th and 12^th graders annually in approximately 127 public and private schools in the coterminous US, using self-administered tablet and paper-and-pencil questionnaires in classrooms. The samples analyzed in this study consisted of high school 10^th and 12^th grade students, modal ages 16 and 18 respectively, from sixteen independent cohorts (school years 2005 to 2020), and the MTF study used a multi-stage sampling procedure in each year. Corrective weighting was used in the analyses presented in this study to account for the unequal probabilities of selection that occurred at any stage of sampling. More detail about methods and procedures are available.⁵

The modal student response rate for high school 10^th grade students was 88% and for 12^th graders was 82% from 2005 to 2020. To increase the construct coverage, MTF divides much of the questionnaire content into different questionnaire forms which are randomly distributed within classrooms. This approach results in four and six nationally representative subsamples each year for 10^th and 12^th graders, respectively. The measures most relevant for this study were asked on selected forms. This study focuses on the cross-sectional subsamples receiving these selected forms within each year cohort. Institutional Review Board approval was granted for this study at the university of the first author.

Measures

Prescription stimulant therapy for ADHD

Prescription stimulant therapy for ADHD was measured by asking respondents if they had ever taken a prescription stimulant medication under a doctor’s supervision for ADHD such as Ritalin^® [MPH], Adderall^® [dextroamphetamine and amphetamine], Concerta^® [extended-release MPH)], Dexedrine^® [dextroamphetamine], and/or other MPH formulations. Respondents were told these drugs do not include non-stimulants.

Age of onset of stimulant therapy for ADHD

Age of onset of stimulant therapy for ADHD was measured by asking respondents how old they were when they first started using one of these prescription stimulant medications for ADHD under a doctor’s supervision. Age of onset responses were categorical and coded as follows: (1) 9 years of age or less, (2) 10–14 years of age, and (3) 15 years or older.

Duration of exposure of stimulant therapy for ADHD

Duration of exposure of stimulant therapy for ADHD was measured by asking respondents how many years they used stimulant medications for ADHD under a doctor’s supervision. Duration responses were categorical and coded as follows: (1) less than 1 year, (2) 1 year, (3) 2 years, (4) 3–5 years, and (5) 6 or more years.

Non-stimulant therapy for ADHD

Non-stimulant therapy for ADHD was measured by asking respondents if they had ever taken a non-stimulant prescription medication under a doctor’s supervision for ADHD such as Strattera^® [atomoxetine], Intuniv^® [guanfacine], Wellbutrin^® [bupropion], and/or Provigil^® [modafinil].

Based on prior clinical and epidemiological research, we created the following 15 mutually exclusive groups for purposes of analysis^4,27,29,30:

Stimulant therapy onset for ADHD during pre-school/early elementary school (aged 9 or younger):

• 16 or more years duration,
• 23–5 years duration,
• 32 years duration,
• 41 year duration, or
• 5Less than 1 year duration.

Stimulant therapy onset for ADHD during late elementary/middle school (10–14 years):

• 66 or more years duration,
• 73–5 years duration,
• 82 years or less duration,
• 91 year duration, or
• 10Less than 1 year duration.

Stimulant therapy onset for ADHD during high school (15+ years):

• 112 years or more duration,
• 121 year duration, or
• 13Less than 1 year duration.
• 14Non-stimulant therapy for ADHD only.
• 15Population controls consisting primarily of non-ADHD youth and some ADHD youth who have not received medication therapy for ADHD in their lifetime—estimated to be 3% of the population controls based on national estimates of untreated ADHD.⁴

Prescription stimulant misuse

Prescription stimulant misuse was assessed by asking respondents on how many occasions (if any) they used prescription stimulants on their own, without a doctor’s orders during the past 12 months. Respondents were provided a list of commonly misused prescription stimulants and indications. Respondents were instructed not to include any non-prescription drugs such as over-the-counter diet pills or stay-awake pills. The response scale options ranged from (1) No occasions to (7) 40 or more occasions.

Illicit stimulant use

Illicit stimulant use included cocaine (crack or any other form) and methamphetamine. Each of these drug use behaviors were assessed with a separate item that asked respondents on how many occasions (if any) they used [cocaine or methamphetamine] during the past 12 months. The response scale for each of these items ranged from (1) No occasions to (7) 40 or more occasions.

Covariates

Covariates included sex, race/ethnicity, grade-level, parents’ level of education, urbanicity, US region, cohort year, grade point average (GPA), truancy (whether respondent skipped a full day of school in the past month), past 30-day cigarette use (10^th and 12^th grade), past two-week binge drinking (10^th and 12^th grade), past-year marijuana use (10^th and 12^th grade), whether they indicated taking both stimulant and non-stimulant medication to treat ADHD, and whether they indicated stopping the use of stimulant or non-stimulant medication to treat ADHD.

Data analysis

Binary logistic regression models were used to estimate odds ratios (OR), adjusted odds ratios (AOR), and 95% confidence intervals (CI) to assess if early onset/late onset and longer duration/shorter duration of stimulant therapy for ADHD was associated with increased odds of cocaine, methamphetamine, or prescription stimulant misuse relative to population controls (and early onset/long duration [age 9 or younger/6 years or more duration] of stimulant therapy). We used the mutually exclusive 15 category variables presented above that measured both onset and duration in order to adequately model both onset and duration to: (1) address issues of multicollinearity (ie, later onset is negatively associated with longer duration r = −0.371), (2) address that in the older age category there are substantial ceiling effects on duration of use, and (3) include meaningful comparison groups for the population controls and non-stimulant medication only group. Accordingly, in the fully adjusted models we ran one set of analyses (1) to compare each stimulant/non-stimulant therapy group to the population controls, and another set to (2) compare each stimulant/non-stimulant therapy group to the group with the earliest and longest duration for stimulant therapy (ie, stimulant therapy onset for ADHD at age 9 or younger and 6 years or more duration) to help control for potential confounders (eg, ADHD) against controls.

Stata 17.0 (StataCorp LLC, College Station, Texas) was used to conduct all analyses. Due to missing data on some of the items, analyses were conducted using listwise deletion (item missingness ranged from 0.0% to 10.8%, see Table 1). Based on differences between missing and retained participants (see Supplemental Table S1), additional analyses for the fully adjusted models were also conducted using full information maximum likelihood (FIML) estimation to verify the results based on the complete case analyses. All analyses applied custom weights provided by MTF to account for the probability of selection into the sample.

Table 1.

Sample characteristics (N = 150,395)

	% (n)	% missing (n)
Prescription stimulant therapy for ADHD
No stimulant therapy for ADHD	91.8 (123,582)	10.4 (15,876)
Stimulant therapy for ADHD	8.2 (10,937)
Non-stimulant therapy for ADHD
No non-stimulant therapy for ADHD	94.3 (126,378)	10.8 (16,502)
Non-stimulant therapy for ADHD	5.7 (7515)
Sex
Male	49.0 (70,332)	4.9 (7266)
Female	51.0 (72,797)
Race/ethnicity
White	55.0 (83,061)	0.0 (0)
Black	11.6 (17,225)
Hispanic	15.6 (22,926)
Other	17.8 (27,183)
Grade level
10th	52.1 (78,361)	0.0 (0)
12th	47.9 (72,034)
GPA
B- or higher	79.1 (114,378)	4.6 (6710)
C+ or lower	20.9 (29,307)
Skipped school
No	77.7 (107,725)	8.0 (11,999)
Yes	22.3 (30,671)
Parents level of education
Less than a college degree	45.8 (61,447)	7.8 (11,265)
College degree or higher	54.2 (77,683)
Urbanicity
Large MSA (urban)	32.0 (55,053)	0.0 (0)
Other MSA (suburban)	47.6 (66,145)
Non-MSA (rural)	20.5 (29,197)
US region
Northeast	18.5 (30,834)	0.0 (0)
Midwest	23.6 (35,949)
South	35.5 (51,035)
West	22.4 (32,577)
Cohort year
2005–2009	34.6 (51,993)	0.0 (0)
2010–2014	31.8 (47,844)
2015–2020	33.6 (50,558)
Cigarette use (past 30 days)
No	87.5 (128,022)	3.0 (4393)
Yes	12.5 (17,980)
Binge drinking (past two weeks)
No	82.3 (113,686)	7.7 (11,499)
Yes	17.7 (25,210)
Marijuana use (past year)
No	81.6 (116,897)	4.4 (6461)
Yes	18.4 (27,037)

Note: ADHD = attention-deficit/hyperactivity disorder; GPA = grade point average; MSA = metropolitan statistical area. Unweight sample sizes are provided. Percentages are weighted.

RESULTS

As shown in Table 1, the prevalence of stimulant therapy for ADHD among US 10^th and 12^th grade students was 8.2% (10^th grade 7.9%, 12^th grade 8.5%). Among those who reported stimulant therapy for ADHD, an estimated 36.7% (10^th grade 37.2%, 12^th grade 35.9%) initiated at age 9 years or younger; 36.7% (10^th grade 41.8%, 12^th grade 31.8%) initiated during ages 10–14 years; and 26.5% (10^th grade 21.0%, 12^th grade 32.3%) initiated during age 15 years or older. In addition, approximately 3.3% (10^th grade 3.5%, 12^th grade 3.2%) reported only non-stimulant therapy for ADHD.

Table 2 shows the prevalence of stimulant or non-stimulant therapy for ADHD. The largest group among respondents who had a history of ADHD stimulant therapy was students who started at age 9 or younger and who took these types of medications for 6 years or longer (18.4%); the second largest group was among students who started ADHD stimulant medications at age 15 or older and who took these types of medication for less than one year (13.3%).

Table 2.

Stimulant or non-stimulant therapy for ADHD (N = 150,395)

	Full sample	Stimulant therapy only
	% (n)	% (n)
Stimulant therapy onset for ADHD at age 9 or younger
6 years or more duration	1.5 (1915)	18.4 (1915)
3–5 years duration	0.5 (678)	6.3 (678)
2 years duration	0.3 (361)	3.5 (361)
1 year duration	0.2 (228)	2.1 (228)
Less than 1 year duration	0.5 (658)	6.3 (658)
Stimulant therapy onset for ADHD at ages 10–14
6 years or more duration	0.6 (719)	6.9 (719)
3–5 years duration	1.0 (1305)	12.0 (1305)
2 years duration	0.5 (697)	6.2 (697)
1 year duration	0.3 (340)	3.2 (340)
Less than 1 year duration	0.7 (890)	8.5 (890)
Stimulant therapy onset for ADHD at age 15 or older
2 years or more duration	0.7 (962)	8.9 (962)
1 year duration	0.3 (458)	4.3 (458)
Less than 1 year duration	1.1 (1455)	13.3 (1455)
Non-stimulant therapy for ADHD only	3.3 (4409)
Population controls (non-ADHD and unmedicated ADHD)	88.6 (117,089)

Note: ADHD = attention-deficit/hyperactivity disorder.

Tables 3 and 4 provide the descriptive statistics, ORs, and AORs assessing if early onset/late onset and longer duration/shorter duration stimulant therapy for ADHD were associated with increased odds of cocaine, methamphetamine, or prescription stimulant misuse. When assessing the fully adjusted models (Table 4), the odds were higher for groups with later onset and shorter duration stimulant therapy (eg, stimulant therapy onset for ADHD at age 9 or younger with 6 years or more duration [AOR=1.56, 95% CI=1.20–2.04] versus stimulant therapy onset for ADHD at age 15 or older with less than 1 year duration [AOR=3.87, 95% CI=3.07–4.87]). When examining youth who initiated early onset with long duration of ADHD stimulant therapy as the reference group (ie, ADHD stimulant medications at age 9 or younger and who took these types of medications for 6 years or longer), groups with later onset and shorter duration had higher odds of indicating past-year prescription stimulant misuse (eg, stimulant therapy onset for ADHD at age 15 or older with less than 1 year duration [AOR=2.47, 95% CI=1.80–3.38]). The odds for the intermediate duration treatment subgroups (2–5 years), regardless of age of onset, tended to have intermediate levels of illicit stimulant use and prescription stimulant misuse; mostly falling between shorter duration and longer duration within each age of onset group (ie, age 9 or younger and 10–14 years of age).

Table 3.

Estimated prevalence of past-year stimulant misuse based on adolescents’ history of medication therapy for ADHD

	Past-year Rx stimulant misuse	Past-year Rx stimulant misuse	Past-year cocaine use	Past-year cocaine use	Past-year meth use	Past-year meth use
	(n = 130,340)	(n = 130,340)	(n = 130,433)	(n = 130,433)	(n = 100,791)	(n = 100,791)
Stimulant or non-stimulant therapy for ADHD	% (95% CI)	ORa (95% CI)	% (95% CI)	ORa (95% CI)	% (95% CI)	ORa (95% CI)
Stimulant therapy onset for ADHD at age 9 or younger
6 years or more duration	11.4 (9.4–12.8)	2.06 (1.72–2.46)	3.6 (2.7–4.7)	1.74 (1.31–2.32)	2.8 (1.9–4.1)	3.64 (2.45–5.40)
3–5 years duration	13.1 (10.4–16.3)	2.50 (1.93–3.24)	5.7 (4.1–7.8)	2.85 (2.02–4.03)	2.3 (1.3–4.2)	3.01 (1.62–5.61)
2 years duration	12.0 (8.9–15.9)	2.26 (1.63–3.14)	7.4 (4.6–11.7)	3.78 (2.30–6.23)	2.9 (1.5–5.6)	3.83 (1.94–7.56)
1 year duration	14.2 (10.0–19.6)	2.72 (1.84–4.04)	6.6 (4.1–10.7)	3.24 (1.92–5.48)	3.0 (1.2–7.2)	3.94 (1.58–9.81)
Less than 1 year duration	15.1 (11.9–18.8)	2.95 (2.25–3.88)	9.3 (6.8–12.6)	5.04 (3.54–7.17)	4.7 (3.0–7.2)	6.21 (3.88–9.93)
Stimulant therapy onset for ADHD at ages 10–14
6 years or more duration	12.4 (9.9–15.5)	2.34 (1.81–3.03)	5.9 (4.3–8.2)	2.84 (2.00–4.03)	3.1 (1.9–5.1)	4.09 (2.42–6.88)
3–5 years duration	21.2 (18.6–24.0)	4.50 (3.82–5.30)	8.4 (6.7–10.4)	4.46 (3.46–5.75)	5.6 (4.0–7.9)	7.53 (5.18–10.9)
2 years duration	24.2 (20.7–28.2)	5.36 (4.36–6.59)	8.0 (6.1–10.5)	4.33 (3.19–5.87)	4.9 (3.4–7.2)	6.59 (4.36–9.96)
1 year duration	23.1 (18.1–28.8)	5.04 (3.73–6.79)	9.8 (6.7–14.1)	5.56 (3.67–8.42)	5.3 (2.7–10.1)	7.07 (3.49–14.3)
Less than 1 year duration	24.1 (17.4–26.0)	5.35 (4.45–6.42)	9.7 (7.7–12.1)	5.50 (4.27–7.09)	5.0 (3.5–7.2)	6.66 (4.56–9.73)
Stimulant therapy onset for ADHD at age 15 or older
2 years or more duration	21.5 (18.6–22.6)	4.45 (3.71–5.34)	9.2 (7.2–11.6)	4.28 (3.27–5.61)	4.4 (2.8–6.9)	5.81 (3.60–9.36)
1 year duration	25.0 (20.6–30.0)	5.49 (4.28–7.06)	8.1 (5.7–11.2)	3.96 (2.73–5.74)	3.1 (1.4–7.1)	4.12 (1.75–9.66)
Less than 1 year duration	26.0 (23.4–28.8)	5.83 (5.06–6.72)	9.2 (7.6–11.1)	4.77 (3.84–5.92)	3.6 (2.5–5.3)	4.79 (3.24–7.09)
Non-stimulant therapy for ADHD only	14.1 (12.8–15.3)	2.72 (2.45–3.02)	5.7 (4.9–6.6)	2.96 (2.52–3.47)	3.9 (3.1–4.8)	5.11 (4.08–6.39)
Population controls (non-ADHD and unmedicated ADHD)	5.6 (5.5–5.9)	Reference	2.1 (1.9–2.2)	Reference	0.8 (0.7–0.9)	Reference

Note: ADHD = attention-deficit/hyperactivity disorder; Rx = prescription; meth = methamphetamine; CI = confidence interval; OR = odds ratio. Unweighted sample sizes are provided.

^aUnadjusted models control for grade level (ie, 10^th grade versus 12^th grade).

Table 4.

Adjusted odds ratios of past-year stimulant misuse based on adolescents’ history of medication therapy for ADHD

	Past-year Rx stimulant misuse	Past-year Rx stimulant misuse	Past-year cocaine use	Past-year cocaine use	Past-year meth use	Past-year meth use
	(n = 109,027)	(n = 109,027)	(n = 109,032)	(n = 109,032)	(n = 83,377)	(n = 83,377)
Stimulant or Non-Stimulant Therapy for ADHD	AORa (95% CI)	AORa (95% CI)	AORa (95% CI)	AORa (95% CI)	AORa (95% CI)	AORa (95% CI)
Stimulant therapy onset for ADHD at age 9 or younger
6 years or more duration	1.56 (1.20–2.04)	Reference	1.33 (.927–1.93)	Reference	1.71 (.977–2.99)	Reference
3–5 years duration	1.63 (1.12–2.37)	1.04 (.687–1.58)	1.47 (.872–2.47)	1.09 (.611–1.97)	1.06 (.422–2.66)	.619 (.235–1.63)
2 years duration	1.31 (.797–2.15)	.835 (.493–1.41)	1.45 (.721–2.93)	1.08 (.507–2.32)	1.53 (.530–4.46)	.898 (.287–2.80)
1 year duration	1.85 (1.08–3.15)	1.18 (.675–2.06)	2.03 (.846–4.90)	1.52 (.619–3.73)	2.17 (.559–8.48)	1.27 (.307–5.26)
Less than 1 year duration	1.83 (1.20–2.79)	1.17 (.742–1.84)	2.43 (1.41–4.17)	1.81 (.987–3.33)	1.79 (.771–4.15)	1.04 (.383–2.84)
Stimulant therapy onset for ADHD at ages 10–14
6 years or more duration	1.34 (.915–1.96)	.855 (.549–1.33)	1.86 (1.23–2.79)	1.38 (.831–2.31)	1.80 (.890–3.64)	1.05 (.447–2.47)
3–5 years duration	2.77 (2.20–3.49)	1.76 (1.28–2.44)	2.12 (1.51–2.97)	1.58 (.984–2.53)	3.06 (1.75–5.33)	1.78 (.846–3.77)
2 years duration	3.04 (2.19–4.22)	1.94 (1.35–2.79)	1.78 (1.09–2.90)	1.32 (.764–2.30)	1.64 (.767–3.49)	.957 (.412–2.22)
1 year duration	3.40 (2.10–5.51)	2.17 (1.29–3.64)	3.33 (1.89–5.85)	2.48 (1.34–4.58)	2.79 (.945–8.27)	1.63 (.515–5.18)
Less than 1 year duration	3.93 (2.89–5.34)	2.50 (1.71–3.65)	3.25 (2.13–4.92)	2.42 (1.46–3.99)	2.51 (1.20–5.22)	1.46 (.624–3.44)
Stimulant therapy onset for ADHD at age 15 or older
2 years or more duration	2.16 (1.65–2.83)	1.38 (.979–1.94)	1.83 (1.27–2.64)	1.37 (.842–2.23)	1.41 (.746–2.69)	.828 (.359–1.09)
1 year duration	3.37 (2.44–4.67)	2.15 (1.45–3.18)	1.86 (1.14–3.03)	1.39 (.784–2.47)	.956 (.329–2.77)	.558 (.179–1.73)
Less than 1 year duration	3.87 (3.07–4.87)	2.47 (1.80–3.38)	2.34 (1.66–3.29)	1.74 (1.09–2.77)	1.99 (1.14–3.47)	1.16 (.558–2.43)
Non-stimulant therapy for ADHD only	1.90 (1.67–2.17)	1.21 (.910–1.62)	1.81 (1.47–2.22)	1.35 (.889–2.05)	2.68 (1.95–3.68)	1.56 (.832–2.94)
Population controls (non-ADHD and unmedicated ADHD)	Reference	.637 (.491–.828)	Reference	.746 (.516–1.07)	Reference	.584 (.333–1.02)

Note: ADHD = attention-deficit/hyperactivity disorder; Rx = prescription; meth = methamphetamine; AOR = adjusted odds ratio; CI = confidence interval. Unweighted sample sizes are provided.

^aAdjusted models control for the following: sex, race/ethnicity, grade level, grade point average (GPA), whether respondent skipped a full day of school, parents’ level of education, urbanicity, US region, cohort year, past 30-day cigarette smoking, past two-week binge drinking, past 30-day marijuana use, whether they indicated taking both ADHD and non-ADHD medication to treat ADHD and whether they indicated stopping the use of stimulant medication to treat ADHD.

Table 4 also shows that the early onset (age 9 or younger) with long duration (6 years or more duration) group had similar odds of past-year cocaine use (AOR=1.33, 95% CI=0.927–1.93) and methamphetamine use (AOR=1.71, 95% CI=0.977–2.99) when compared to population controls, while the later onset/shorter duration groups had higher odds of both cocaine and methamphetamine use when compared to population controls (eg, stimulant therapy onset for ADHD at age 15 or older with less than 1 year duration [cocaine AOR=2.34, 95% CI=1.66–3.29; methamphetamine AOR=1.99, 95% CI=1.14–3.47]). Additionally, groups with later onset and shorter duration of stimulant therapy for ADHD had higher odds of indicating past-year cocaine use when compared to the early onset/long duration of ADHD stimulant therapy group (eg, stimulant therapy onset for ADHD at age 15 or older with less than 1 year duration [AOR=1.74, 95% CI=1.09–2.77]). The odds of past-year methamphetamine use were similar across each of the stimulant therapy groups.

No differences in past-year cocaine, methamphetamine, and prescription stimulant misuse were found between individuals who only used non-stimulant therapy for ADHD and individuals who started ADHD stimulant medications at age 9 or younger and for a duration of 6 years or longer. Notably, individuals who only used non-stimulant therapy for ADHD had higher odds of past-year cocaine use (AOR = 1.81, 95% CI = 1.47–2.22), methamphetamine use (AOR = 2.68, 95% CI = 1.95–3.68), and prescription stimulant misuse (AOR = 1.90, 95% CI = 1.67–2.17) when compared to population controls.

Finally, both grade of respondent and cohort year were associated with past-year cocaine, methamphetamine, and prescription stimulant misuse (results not shown). In particular, compared to 10^th graders, 12^th graders had higher odds of indicating past-year cocaine use (AOR=1.29, 95% CI=1.15–1.45) but lower odds of indicating past-year prescription stimulant misuse (AOR=0.787, 95% CI=0.729–0.849) and methamphetamine use (AOR=0.810, 95% CI=0.657–0.999). Moreover, compared to earlier cohorts (ie, 2005–2009), later cohorts had higher odds of indicating past-year prescription stimulant misuse (2010–2014, AOR=1.12, 95% CI=1.03–1.22; 2015–2020, AOR=1.11, 95% CI=1.01–1.21) and lower odds of indicating both past-year cocaine (2010–2014, AOR=0.555, 95% CI=0.488–0.631; 2015–2020, AOR=0.638, 95% CI=0.552–0.736) and methamphetamine use (2010–2014, AOR=0.567, 95% CI=0.458–0.701; 2015–2020, AOR=0.328, 95% CI=0.240–0.448). Additional analyses found no significant interaction effects between stimulant or non-stimulant therapy for ADHD (the 15 category variables) and grade level, or between stimulant or non-stimulant therapy for ADHD (the 15 category variables) and cohort when predicting past-year cocaine, methamphetamine, and prescription stimulant misuse. Finally, additional analyses found similar results when examining associations between stimulant or non-stimulant therapy for ADHD (the 15 category variables) and lifetime (rather than annual) cocaine, methamphetamine, and prescription stimulant misuse. Sensitivity analyses that excluded the variable assessing use of both stimulant and non-stimulant medications to treat ADHD and/or the variables about stopping use of stimulant or non-stimulant medications to treat ADHD produced similar results to models that included these variables. Additional analyses were conducted to examine the frequency of stimulant misuse, and results were similar for infrequent and more frequent misuse (see Supplemental Tables S2 and S3). Moreover, the results from the fully adjusted models using FIML provided similar results confirming that adolescents with earlier initiation and longer duration of stimulant therapy had lower odds of stimulant misuse and cocaine use when compared to their peers who initiated stimulant therapy at later ages with shorter duration (see Supplemental Table S4).

DISCUSSION

This is the first study to provide detailed national-level estimates of the relationships among age of onset of stimulant therapy for ADHD, duration of stimulant therapy for ADHD, and stimulant misuse behaviors involving cocaine, methamphetamine, and prescription stimulant misuse during adolescence. The present study found that 11.5% of US 10^th and 12^th grade students had used stimulant or non-stimulant therapy for ADHD in their lifetime. While the present study could not examine true causality, the associations provide support for Hypothesis 1A: youth who initiated early onset (≤9 years old) with longer duration (≥6 years) stimulant therapy for ADHD had significantly lower odds of cocaine and prescription stimulant misuse during adolescence relative to youth who initiated stimulant therapy for ADHD later (≥10 years old) with shorter duration (<1 year). Because we could not determine the temporal order of stimulant therapy and cocaine and prescription stimulant misuse, it is possible that cocaine and prescription stimulant misuse occurred before stimulant therapy, especially for the late onset and short duration subgroup. In addition, there was support for Hypothesis 1B that those who had intermediate duration treatment (2–5 years) would have intermediate levels of illicit stimulant use and prescription stimulant misuse. The findings suggested an inverse relationship between years of stimulant therapy and outcomes for illicit and prescription stimulant misuse: the longer the duration of stimulant therapy, the lower the risk for illicit stimulant use. Some experts have asserted that early detection and appropriate medication management may decrease core ADHD symptoms such as impulsivity and promote adaptive behaviors that could reduce SUDs and other addictive behaviors later in life.³⁷

While the findings indicate no statistically significant differences in the adjusted odds of cocaine or methamphetamine use between youth who initiated stimulant therapy for ADHD early (≤9 years old) with longer duration (≥6 years) and population controls, more prospective research is needed to examine this association noted in Hypothesis 2. While multiple studies have shown that ADHD is itself an important risk factor for illicit stimulant misuse and SUD,^{5,12,15,20–24} the present study offers promising results for children who receive early stimulant therapy for ADHD. These findings support data derived from smaller clinical studies that early initiation of stimulant treatment for ADHD is not associated with an increased risk of illicit stimulant misuse relative to later onset of treatment, and that the resulting risk is actually similar to that in the general population.³⁰ These results may contrast with work that has examined longer duration of treatment involving prescription opioids.^38,39 While not addressed in this paper, there is a need for more prospective research to examine the longitudinal relationships between longer duration of treatment for benzodiazepines, opioids, stimulants, and risk for polysubstance use, SUD, and overdose.

We found support for Hypothesis 3, as youth who initiated stimulant therapy for ADHD later (≥10 years) with shorter duration (<1 year) had significantly greater odds of cocaine, methamphetamine, or prescription stimulant misuse during adolescence relative to population controls. One potential explanation for this finding could be reflective of confounding of association of later, shorter treatment with stimulant misuse by common causal factors associated with impaired access and adherence to care. Older adolescents may have already initiated substance use/misuse or developed SUD symptoms during secondary school before or around the same time of stimulant therapy initiation which could be a marker of a more severe ADHD/SUD phenotype. Some research indicates a considerable portion of prescription stimulant misuse during late adolescence and young adulthood is driven by cognitive enhancement, self-medication for untreated ADHD symptoms, neuropsychological dysfunction, peer diversion, and reservoirs of leftover medication.^5,40 For instance, a recent national study found that 70%–75% of all prescription stimulant misuse was motivated only for cognitive enhancement in these age groups.⁴⁰ These findings warrant additional research to examine prospective associations because the later onset group did not have time to obtain longer treatment duration. More attention regarding risk reduction strategies for prescription stimulants based on their addictive potential⁸ and potential links to stimulant-involved drug overdoses in the US is needed.^9,25 Furthermore, this information has important clinical implications regarding enhanced parental monitoring, screening, storage, disposal, and patient education regarding the benefits and limitations of ADHD medications.⁴¹

It should be highlighted that the odds of prescription stimulant misuse were higher for the non-stimulant treatment group as well as all groups who were treated with stimulant medication for ADHD compared to population controls, even those with early onset (≤9 years old) with longer duration (≥6 years) treatment. ADHD itself, its psychosocial sequelae (eg, bullying), or comorbid disorders (eg, conduct disorder) could be conferring the increased risk for prescription stimulant misuse rather than treatment with stimulants.³⁰ The higher risk of stimulant misuse among older adolescents could be further driven by increased access and availability of prescription stimulants as well as older adolescents assuming more responsibility for their medication management.

The present study revealed new key findings regarding non-stimulant therapy for ADHD. First, approximately 1 in 18 US 10^th and 12^th grade students reported non-stimulant therapy for ADHD, including 3.3% who reported only non-stimulant therapy, which is consistent with previous research.⁴ Second, youth who reported only non-stimulant therapy for ADHD did not differ significantly from youth who reported early onset (≤9 years old) with long duration (≥6 years) of stimulant therapy for ADHD in terms of the likelihood of cocaine, methamphetamine, or prescription stimulant misuse. These findings regarding non-stimulant therapy also further support the supposition that early onset of stimulant therapy for ADHD with long duration does not increase the likelihood of later illicit stimulant use. We replicated previous findings that starting prescription stimulants later and for shorter treatment duration in children with ADHD was associated with higher risks for stimulant misuse. The reasons for this may be: (1) late/undertreated ADHD and lack of well-described preventive aspects of treating ADHD and later SUD; (2) attempts to self-medicate one’s ADHD; (3) development of sequelae of ADHD that independently predict stimulant misuse because of lack of earlier treatment; and (4) that the stimulant misuse may have started prior to, or commensurate with, the addition of stimulant therapy of ADHD. These findings suggest prospective research is needed that examines youth treated with non-stimulant medication for ADHD and accounts for age of onset and duration of non-stimulant therapy.

This study has several strengths that build upon previous literature examining stimulant therapy for ADHD and substance use. First, the MTF study measures large national samples and includes detailed questions regarding medication therapy for ADHD (eg, age of onset, duration, and medication type) and stimulant misuse that have remained the same over time. Second, the large heterogeneous MTF sample allowed for subgroups to be defined based on age of onset and duration of stimulant therapy for ADHD that are often too small to examine in probability-based national studies. Third, the inclusion of multiple grade levels (10^th and 12^th grade) and cohorts (2005–2020) allowed us to examine associations over different developmental and time periods. While we found that the grade level of respondent and cohort year were associated with past-year cocaine, methamphetamine, and prescription stimulant misuse, we found no significant interaction effects between stimulant or non-stimulant therapy for ADHD (the 15 category variables) and grade level, or between stimulant or non-stimulant therapy for ADHD (the 15 category variables) and cohort when predicting past-year cocaine, methamphetamine, and prescription stimulant misuse. Finally, the assessment of non-stimulant therapy for ADHD in the MTF study permitted the youth treated with stimulant medication for ADHD to be compared to a treated group of ADHD youth without any history of using prescription stimulants.

Limitations of the MTF study include the typical limitations of large-scale survey research using self-administered surveys and retrospective assessment, including possible under-reporting of sensitive information and different methods for assessing psychiatric disorders than clinical settings. Important segments of the US youth population were missing from the MTF data collected each year such as homeschooled youth, those absent from class at the time of data collection, and youth who have dropped out of school. Although self-report data in the MTF generally have been found to be reliable and valid, studies suggest that misclassification and under-reporting of substance use does occur.⁵ The MTF study attempted to minimize such bias by utilizing conditions that past research has shown improves the validity and reliability of substance use data collected via self-report surveys, such as explaining the relevance of the study and informing potential respondents about voluntary participation and anonymity.⁵ In the MTF study, no adjustments are made to correct for any under-reporting; thus, results from the present study may be conservative and underreport the actual prevalence of sensitive behaviors. The MTF study does not assess some factors associated with stimulant misuse (eg, ADHD severity, adverse childhood experiences). The lack of an ADHD severity measure represents an important limitation because ADHD severity is likely related to the age of onset, duration, and type of ADHD medication (stimulant or non-stimulant). The MTF study also did not separate amphetamine from methylphenidate treatments —which is important given potentially different misuse liabilities —and did not assess age of onset for ADHD. The cross-sectional nature of the study limited our ability to establish a causal link between medication therapy for ADHD and substance use. In addition, one of the reference categories (population controls) combines primarily youth without ADHD and a small proportion of youth with ADHD who did not receive medication for ADHD (stimulant or non-stimulant therapy for ADHD). These two categories are heterogeneous in their risk for stimulant misuse and SUD and future work should consider examining them separately. Finally, while the results from the fully adjusted models using FIML found relatively consistent results with the analyses using complete case analysis, differences between the two modeling approaches should be interpreted with caution given the data were not missing at random. Taken together, these factors warrant further fine-grained evaluation in future prospective studies with continuous measures involving age of onset, dose, duration, and formulation. Nevertheless, the age of onset of stimulant therapy for ADHD findings in the present study are consistent with previous clinical and epidemiological studies that found early initiation of stimulant treatment for ADHD is not associated with elevated SUD risk.^10,11

CONCLUSION

The findings of this study provide new insights for informing future prescribing practices, monitoring, and research. The results suggest that early onset and longer duration of stimulant therapy for ADHD are associated with less cocaine or prescription stimulant misuse in late adolescence relative to later onset and shorter duration of stimulant therapy for ADHD. There is growing evidence that initiation of ADHD stimulant therapy in secondary school or later may represent a sensitive developmental period that deserves greater clinical and research attention.^26,29,30 These findings have particular relevance given the increases in prescribing stimulants among adults in the US with virtually no national data examining subsequent stimulant misuse or SUD. Additional prospective studies with large samples of ADHD and non-ADHD youth are necessary to further validate the associations found in the present study using within-subject comparison of risk before and after stimulant therapy and between-subject analyses within individuals with ADHD accounting for additional covariates (eg, severity of illness). The findings of the present study reinforce the importance of clinicians initiating an evaluation for ADHD among children exhibiting possible ADHD symptoms. Adolescents with later initiation and/or new onset stimulant treatment for ADHD need to be carefully monitored for stimulant misuse.

Key points.

• Approximately 8.2% of US youth received stimulant therapy for ADHD before completing high school.

• Over 10% of youth reported past-year prescription stimulant misuse (PSM).

• Early onset and longer duration of ADHD stimulant therapy had significantly lower odds of cocaine or PSM relative to youth with later onset and shorter duration of ADHD stimulant therapy.

• No differences in cocaine, methamphetamine, and PSM were found between youth who only used non-stimulant therapy for ADHD relative to youth with early stimulant therapy and for longer duration.

• Adolescents with later initiation and/or shorter duration of ADHD stimulant therapy should be monitored for stimulant misuse.

Data Sharing Statement

This study contains the results of secondary analysis of the USA Monitoring the Future (MTF) surveys. The authors followed university and MTF protocol regarding access to and analysis of the data for this study. Data is not available without written consent from MTF and interested researchers can apply for MTF panel data access through the US National Addiction & HIV Data Archive Program (NAHDAP) at the University of Michigan. More information may be found here: https://www.icpsr.umich.edu/web/NAHDAP/studies/37072