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Methylphenidate doses in Attention Deficit/

Hyperactivity Disorder and comorbid
substance use disorders
Charlotte Skoglunda,n, Lena Brandtb, Brian D’Onofriod,
Henrik Larssonc, Johan Francka

a
Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Norra Stationsgatan
69, SE-113 64 Stockholm, Sweden
b
Center for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Department of
Medicine, Solna, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
c
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77
Stockholm, Sweden
d
Department of Psychological and Brain Sciences Indiana University, 1101 East 10th Street, Bloomington,
IN 47405, USA

Received 26 July 2016; received in revised form 15 July 2017; accepted 30 August 2017

KEYWORDS Abstract
Methylphenidate; Patients with Attention Deficit/Hyperactivity Disorder (ADHD) and comorbid Substance Use
Drug prescription; Disorders (SUD) are increasingly being treated with central stimulant medication despite
Substance use limited evidence for its effectiveness. Lack of longitudinal follow-up studies of dosing and
disorder adverse effects has resulted in conflicting treatment guidelines. This study aims to explore
whether individuals with ADHD and comorbid SUD are treated with higher stimulant doses than
individuals with ADHD only, and whether doses increase over time as a sign of tolerance, a core
symptom of addiction.
Information on methylphenidate doses for 14 314 Swedish adults, including 4870 individuals
with comorbid SUD was obtained through linkages of Swedish national registers between 2006
and 2009. Differences in doses between patients with and without SUD were estimated using
logistic regression while a linear regression model calculated time trends in mean doses.
Individuals with SUD were prescribed higher methylphenidate doses than those without
(ORday365; 2.12, 95% CI 1.81–2.47: ORday730 2.65, 95% CI 2.13–3.30). Patients with SUD were,
two years after initiating stimulant treatment, prescribed approximately 40% higher doses
compared to individuals with ADHD only.
The results may suggest a need for increased doses in this population to achieve optimal ADHD
symptom control. A tendency towards increasing doses during the first years of treatment, more
pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate

n
Corresponding author. Fax: +46 8 346563.
E-mail address: charlotte.skoglund@ki.se (C. Skoglund).

http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
0924-977X/& 2017 Published by Elsevier B.V.

Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
2 C. Skoglund et al.
doses due to lack of clinical guidelines. Mean doses stabilized after about two years in both
groups, which does not lend support to continuously increasing tolerance over time.
& 2017 Published by Elsevier B.V.
1. Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is a pre-
valent neurodevelopmental disorder (Wilens and Spencer,
2010), and individuals with ADHD are at increased risk for
Substance Use Disorders (SUD) (van Emmerik-van
Oortmerssen et al., 2012). Despite a substantial overlap
and signs of common pathophysiological mechanisms (Frodl,
2010) little is known about how patients with ADHD and
comorbid SUD can be safely and effectively treated (Cunill
et al., 2015).
It is well established that pharmacological treatment of
ADHD using stimulant medication improves ADHD core
symptoms (Faraone and Buitelaar, 2010, Faraone and
Glatt, 2010). Methylphenidate is the most commonly used
stimulant medication (NICE guidelines 2008, Kooij et al.,
2010) with an expected treatment response observed in
about 80% of the patients (Pliszka, 2007). Serious adverse
effects are rarely associated with stimulant medication use
(Santosh et al., 2011). However, stimulant medications are
controlled substances (Controlled Substance Act, FDA, 2016)
that increase dopamine levels in brain areas involved in
development of addiction and thus can be recreationally
abused (Wilens et al., 2008). Whereas stimulant treatment
among patients with ADHD has increased in recent years
(McCarthy et al., 2012), few studies have addressed treat-
ment efficacy in individuals with comorbid SUD (Cunill
et al., 2015). Consistent with clinical observations that
individuals with SUD may need substantially higher stimu-
lant doses than those with ADHD only, two recent rando-
mized controlled trials showed significant improvements in
ADHD symptoms and SUD outcomes using higher stimulant
doses than earlier studies (Konstenius et al., 2014, Levin
et al., 2015). Although tolerance is a core symptom of
addiction and may underlie a need for higher initial
stimulant doses in patients with SUD, continuously increas-
ing doses during maintenance pharmacotherapy should raise
concerns as that may reflect a worsening of the SUD.
Societal and clinical concerns or inappropriate beliefs about
the safety of stimulant treatment in individuals with coex-
isting SUD (Cassidy et al., 2015, Faraone and Glatt, 2010,
Kaye and Darke, 2012), lack of longitudinal follow-up
studies of dosing and adverse effects, such as harmful use
and dependence, and a fear that stimulant treatment might
put susceptible individuals at risk for future SUD, relapse or
worsening of ongoing SUD is mirrored in conflicting treat-
ment guidelines (Bolea-Alamanac et al., 2014, Cunill et al.,
2015, NICE 2008).
Observational studies allow for large sample sizes to
relatively small economical costs and can provide long-
itudinal information on changes in prescribed
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
methylphenidate doses over time. In this population-based
cohort study of all 14 314 adults with one or more
prescriptions of methylphenidate between 2006 and 2009
in Sweden, we aimed to explore potential differences in
prescribed stimulant doses between individuals with and
without comorbid SUD, and whether doses increase over
time as a proxy for medication tolerance.
2. Experimental procedures
2.1. Sample
The study was approved by the Research Ethics committee at
Karolinska Institutet, Stockholm, Sweden, protocol no. 2009/5:10,
2009/939-31/5. We obtained data from a record linkage of four
population-based registries in Sweden; personal identification num-
bers enabled accurate linkage. The Swedish Prescribed Drug
Register includes information on drug identity using Anatomical
Therapeutic Chemical (ATC) codes and dates of all prescribed drugs
filled at Swedish pharmacies since July 2005. Each unique prescrip-
tion has a specific dose text describing the quantity and dosage
filled out by the prescribing physician. The National Patient
Register provides data on in-patient psychiatric care since 1973
and outpatient care since 2001, categorized according to diagnostic
coding in the eighth, ninth and tenth revision of the International
Classification of Diseases (ICD-8, ICD-9 and ICD-10). To account for
death and migration all data was linked to the Cause of Death
Register and the Migration Register.
2.2. Measures
2.2.1. Diagnostic categories
A total of 14 314 individuals, aged 18–59, with an initial prescription
of methylphenidate (ATC code for methylphenidate N06BA04 in the
Prescribed Drug register), including 4870 with a diagnosis of SUD,
were included in the main analysis. The National Patient Register
and the Prescribed Drug Register were used to identify patients
diagnosed with alcohol and/or drug use disorders in accordance
with the ICD diagnostic guidelines and/or a prescription including
an ATC code for drugs used exclusively in the treatment of SUD.
Alcohol use disorder was defined using ICD codes from the National
Patient Register (ICD-8: 291 and 303, ICD-9: 291, 303 and 305A and
ICD-10: F10.0-F10.9) and ATC codes for prescriptions of medications
used in the treatment of alcoholism (N07BB03 (acamprosate),
N07BB04 (naltrexone) and N07BB01 (disulfiram)) from the Pre-
scribed Drug Register. Psychoactive drug abuse was measured by
ICD codes from the National Patient Register (ICD-8: 304, ICD-9:
292, 304 and 305X and ICD-10: F11.0–F16.9 and F18.0–F19.9) and
ATC codes from the Prescribed Drug Register for prescriptions of
medications used in the treatment of drug abuse (N02AE01 (bupre-
norphine), N07BC51 (buprenorphine+naltrexone) and N07BC02
(methadone)). An individual was classified as having SUD or not
when included in the study (at the time of the initial prescription of
methylphenidate). In addition, the National Patient Register
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
provided data on coexisting psychiatric ICD-8, ICD-9 and ICD-10
diagnoses other than alcohol and/or drug use disorders.
2.2.2. Operationalization of doses and treatment periods
Individual daily methylphenidate doses were estimated by means of
the text variable in the Prescribed Drug Register. Each prescription
contains a text variable containing the quantity of medication
prescribed and individualized instructions on how the drug is to be
consumed.
If a prescription of equal dosage was filled before the last
prescription was due to run out, we assumed the first filled
prescription to have been consumed. If prescriptions of different
dosage were filled on the same occasion, we assumed them to have
been consumed simultaneously according to the text variable on
each prescription. The prescribed dose was calculated every 100
days and annual point estimates. We defined a treatment period as
the number of days the prescription would last according to the text
variable on the prescription, plus 25% to avoid individual minor
irregularities in dispensing patterns. During subsequent periods or
those without any new prescription, the patient was assumed to be
off treatment.
To ensure that participants had not been receiving methylphe-
nidate treatment prior to follow up, we used information about
prescription dates six months before start of follow-up at January 1,
2006.
Differences in mean methylphenidate doses between patients
with and without SUD were stratified into 0–72 mg and 472 mg
based on recommendations issued by the British Association for
Psychopharmacology (recommended maximum dose 100 mg)
(Bolea-Alamanac et al., 2014), the US Food and Drug Administration
(recommended maximum dose 72 mg) (Controlled Substance Act,
FDA), the National Institute for Health and Care Excellence
(recommended maximum dose 60 mg) (NICE) and clinical expertise.
Also, Osmotic Release Oral System (OROS) is the most commonly
prescribed methylphenidate formulation in Sweden, and only
commercially available in multiples of 18 mg.
To validate the semi-manual method of extracting doses from the
text variable, an independent clinician proofread 4000 randomly
selected records in the material. A total of 0.3% of the prescriptions
were not coded correctly or were interpreted differently by the
proof-reader.
2.3. Statistical analyses
Descriptive measures and distribution of daily doses in categories
were tabulated for individuals with and without SUD with point
estimates at day 100, day 365, day 730 and day 1095 after the date
of the first filled prescription. Logistic regression models were
calculated for the dependent variable (e.g. methylphenidate dose)
at day 365 and 730. Given the potential confounding effects of
several explanatory variables (e.g. SUD subtype, gender, age,
calendar year of the initial prescription and comorbid psychiatric
diagnoses) these covariates were simultaneously fitted into the
adjusted model. Odds ratios (ORs) with Wald 95% confidence
intervals were presented using the LOGISTICS PROCEDURE, SAS
version 9.4. The development of doses over time in patients with
and without SUD was described in a graph depicting a point
estimate of the mean dosage every 100 days. Time trends in mean
doses were tested with linear regression and described in a graph
depicting a point estimate of the mean dosage every 100 days. The
means were weighted with the inverse of the number of subjects in
treatment at the time. Time was arbitrarily divided into two
periods: 100–600 and 700–1200 days after the initial prescription.
2.3.1. Sensitivity analysis
We performed a sensitivity analysis to test whether individuals with
methylphenidate doses over 72 mg/day actually picked up doses
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
3
corresponding to the one prescribed by the physician. A subsample
of the population with doses over 72 mg/day (N=659) was selected,
and the doses in the Prescribed Drug Register on days 300 and 400
were compared to the total accumulated dose filled by the
pharmacy between days 200 and 400.
3. Results
A sample of 14 314 adults (including 4870 individuals with a
diagnosis of SUD) with a prescription of methylphenidate between
January 1, 2006, and December 31, 2009 was included in the main
analysis (Figure 1). Out of the targeted population, 93% was
monitored during the entire follow-up period (Table 1). The mean
period was approximately 550 days in both populations and allowed
for times during which medication was discontinued or resumed.
Psychiatric comorbidity including personality disorders and conduct
disorder was more prevalent among individuals with comorbid SUD
than among individuals with ADHD only (Table 1).
Table 2 shows that, at day 365, 37.1% of individuals with
comorbid SUD were prescribed methylphenidate doses over 72 mg
compared to 20.6% of those with ADHD only (chi-square po0.0001).
At day 730, 44.4% of individuals with comorbid SUD were prescribed
methylphenidate doses over 72 mg, compared to 22.8% of indivi-
duals with ADHD only (chi-square po0.0001). Among individuals
with SUD, 7.3% had doses exceeding 180 mg/day at day 730,
compared to 1.2% of those with ADHD only (chi-square
po0.0001). Retention to treatment at day 730 was 48% in the
SUD population and 42% in individuals with ADHD only (chi-square
po0.0001). The proportion of patients who had been prescribed
extended release preparations at day 730 was high both in patients
with SUD (86%) and in patients with ADHD only (82%)(chi-square
p=0.01).
ORs for methylphenidate doses exceeding 72 mg/day in indivi-
duals with comorbid SUD and ADHD only are shown in Table 3.
Individuals with SUD were at increased risk for exceeding a daily
dose of 72 mg (ORSUDday365 2.12 and ORSUDday730 2.65). A diagnosis of
drug abuse (DA), a combined diagnosis of both DA and alcohol use
disorder (AUD) and a diagnosis of psychoactive stimulant use (SU)
significantly increased the risk for exceeding a dose of 72 mg/day
(ORDAday365 2.53, ORDAday730 3.09, ORDA + AUDday365 2.53 and ORDA
+ AUDday730 2.97, ORSUday365 3.08, ORSUday730 3.63). The corresponding
risk associated with a diagnosis of AUD only was lower (ORAUDday365
1.49 and ORAUDday730 2.01), indicating that SUD subtype and/or
severity is correlated to methylphenidate dose. Figure 2 shows a
small but significant increase in mean doses (1.1 mg/100 days)
between days 100 and 600 in individuals with ADHD only. The
increase of mean doses in individuals with comorbid SUD was
greater (3.2/100 days) (p-value for interaction 0.001). In contrast
no statistically significant trend in mean doses was observed
between days 700 and 1200 (p=0.30 in the entire population;
p=0.21 in individuals with comorbid SUD and p=0.15 in individuals
with ADHD only).
3.1. Sensitivity analysis
Our sensitivity analysis showed that 90% (95% CI 87.5 to 92.1) of
individuals who were prescribed a daily dose of over 72 mg on days
300 and 400 picked up corresponding daily doses of over 72 mg at
the pharmacy between days 200 and 400.
4. Discussion
This nationwide, register-based cohort study of adult ADHD
patients treated with methylphenidate, shows that patients
with comorbid SUD, two years into stimulant treatment,
4 C. Skoglund et al.

Fig. 1 Flowchart.

were prescribed approximately 40% higher methylphenidate
doses than individuals with ADHD only. Doses in both groups
stabilized during the first two years of treatment.
The findings of higher doses in the ADHD plus SUD group
may indicate that patients with SUD need higher methyl-
phenidate doses to achieve optimal ADHD symptom control.
One interpretation of these findings, supported by the
finding that individuals with a diagnosis of psychoactive
stimulant use were prescribed higher methylphenidate
doses compared to other SUD subtypes, is that individuals
with comorbid SUD might have developed a tolerance to
central stimulants. An increase in tolerance is likely to
result in a need for higher doses and prolonged titration
periods. This would be consistent with two recent rando-
mized controlled trials (Konstenius et al., 2014, Levin et al.,
2015) showing significant improvements in both ADHD
symptoms and SUD outcomes using higher stimulant doses
than earlier studies. If true, this may explain why previous
research have found little evidence for any beneficial
effects of methylphenidate on SUD-related outcomes
(Cunill et al., 2015, Perez-Mana et al., 2013) using doses
recommended by current guidelines (mean doses 62.2 mg/
day) (Bolea-Alamanac et al., 2014, NICE 2008. Kooij et al.,
2010). An alternative explanation for the different doses
could be ADHD subtype, with differences in symptom
severity, or psychiatric comorbidity. Whereas ADHD and
personality disorders frequently co-occur in adult non-SUD
populations (Matthies and Philipsen, 2016), a recent cross-
sectional study also showed that 75% of SUD patients with
ADHD had at least one additional comorbid disorder com-
pared with 37% patients without ADHD (van Emmerik-van
Oortmerssen et al., 2014). As the present dataset cannot be
linked to individual clinical data, this needs to be further
explored in future studies.
Mean doses stabilized over time in both populations at
the end of follow-up even though, among individuals with
comorbid SUD, a continuous increase in mean dose was
observed up to approximately two years of treatment.
Assuming that the initial dosing may have been inadequate,
the tendency towards increasing doses during the first two
years of treatment, more pronounced in individuals with
comorbid SUD, may reflect a reluctance to prescribe
adequate doses due to lack of clinical guidelines, and/or
prescribers’ inappropriate beliefs. The dose-response

Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders 5

symptoms, modulates the pathophysiology of SUD directly,

Table 1 Distribution of study variables across indivi-
or both.
duals with and without comorbid SUD.
Adequate treatment, more specifically adequate dosage,
SUD No SUD may increase the motivation to stay in treatment and
prevent relapses to illegal drug use. While the efficacy of
(n = 4870) (n = 9444) agonist maintenance therapy available for opioid addiction
has been extensively studied (Mattick et al., 2014), sub-
% % stitution treatment for psychoactive stimulant use has been
less investigated (Galloway et al., 2011, Longo et al., 2010,
Follow-up
Mariani et al., 2014, Miles et al., 2013, Tiihonen et al.,
Until December 31, 2009 93.1 93.8
2007). Research targeting the direct effect of central
Censoreda 6.9 6.2
stimulant medication on SUD pathophysiology is as yet
inconclusive (Galloway et al., 2011, Longo et al., 2010,
Observation Miles et al., 2013, Tiihonen et al., 2007). In the present
Mean days (sd) 550.6 (388.6) 549.8 (400.4) study, a diagnosis of drug abuse (DA), a combined diagnosis
of both DA and alcohol use disorder (AUD) and a diagnosis of
psychoactive stimulant use (SU) significantly increased the
Age risk for exceeding a dose of 72 mg/day indicating that SUD
Mean years (sd) 34.6 (10.3) 31.7 (10.5) severity and/or subtype may be correlated to methylphe-
Female 36.1 47.9 nidate dose. Also, at any given time point during the follow-
up, individuals with comorbid SUD had higher adherence to
Psychiatric diagnosis treatment than those with ADHD only. Three years following
Schizophreniab 3.2 0.7 the initial prescription of methylphenidate, 45% of patients
Schizoaffective disorderb 1.1 0.4 with ADHD and SUD, compared to 37% of individuals with
Mood disordersb 38.4 30.6 ADHD only, were still actively picking up their prescriptions.
Bipolar disordersb 10.0 7.28 Population-based register data have several strengths
Anxiety disordersb 50.3 34.4 compared with clinical trials including substantial sample
Eating disordersb 3.7 3.4 sizes representative for the population. Research based on
Personality disordersb 26.9 11.2 nationwide registers can avoid problems arising from refer-
Conduct disorderb 2.4 1.3 ral bias, selective participation, and other threats to
validity and generalizability. Information on SUD was
SUD=Substance Use Disorders. acquired using both ICD-codes from the National Patient
b
ATC code: N05BA, N05CF, N05C. Register and ATC-codes in the Prescribes Drug Register, thus
a
Censored due to; Emigration n=89, Deceased n=138, minimizing the risk of informant and recall bias. Medication
Participation in clinical trial n=5, Prescriptions of dexam-
for ADHD is recorded in the Prescribed Drug Register when a
phetamine or amphetamine n=691
b prescription is filled, and therefore free from recall bias.
ICD8-10 diagnoses: Schizophrenia (ICD-8: 295.0–295.4,
295.6, 295.8–295.9; ICD-9: 295A-295E, 295G, 295W, 295X; The present results need to be interpreted in the light of
ICD-10: F20), Schizoaffective disorder (ICD-8 295.7; ICD-9 some important limitations regarding the diagnostic proce-
295H; ICD-10 F25), Mood disorders (ICD8: 296.2, 298.0, dure of ADHD and SUD, assumptions of individual doses and
300.4; ICD9: 296B, 300E; ICD10: F32–F39), Bipolar disorders duration of active medication. The ascertainment of ADHD
(ICD-8: 296.1, 296.3, 296.8; ICD-9: 296A/C/D/E/W; ICD-10: was predominantly based on prescribed medication unique
F30–F31), Anxiety disorders (ICD8, ICD9: 300; ICD10:F40-48), for the treatment of ADHD. Since the National guidelines for
Eating disorders (ICD8: 306.5; ICD9: 307B/F; ICD10: F50), medication of ADHD, issued by the Swedish National Board
Personality disorders (ICD8, ICD9: 301; ICD10:F60, Conduct of health and Welfare in 2002, stated that medication
disorder (ICD9: 312; ICD-10: F91).
should be reserved for cases where other supportive inter-
ventions have failed, this strategy could probably not avoid
producing false negatives, but we consider bias due to false
relationship of methylphenidate on ADHD symptoms is well positive ADHD diagnosis more unlikely, not least due to the
established in children (Greenhill et al., 2001). Less is strict enforcement of malpractice regulations in Sweden
known about dose-response in adults and inter-individual and the limitation to only psychiatrists and pediatricians
serum concentration variability in relation to ADHD symp- specializing in pediatric neurology to prescribe central
tom control (Ermer et al., 2010), and clinicians are left to stimulants. Due to methodological limitations inherent in
arbitrarily titrate the medication based on the patient's the study design such as lack of clinical information on ADHD
subjective response. Given the lack of objective assessment subtype, symptom severity, dose-response data, and other
procedures, biomarkers or clear treatment guidelines, psychosocial interventions targeting ADHD and/or SUD there
clinicians might be reluctant to increase doses to optimal is limited adjustment for these potential confounders and
levels for individuals with ADHD and SUD due to fear of the results should be interpreted with caution. Also, the
misuse, abuse or diversion (Wilens et al., 2008, Kaye and possibilities of long-term follow up due to collect data from
Darke 2012). three different diagnostic systems (ICD-8, ICD-9 and ICD-10)
An important question that deserves further investigation must be weighted against potential problems arising from
is whether methylphenidate primarily targets ADHD differences in definition of the ADHD and SUD diagnoses
across these three generations of coding systems. Given the

Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
6 C. Skoglund et al.

Table 2 Methylphenidate (MPH); mean daily doses and distribution of doses and formulations over time in individuals with
substance use disorder compared to individuals with ADHD only.

100 daysa 365 daysa 730 daysa 1095 daysa

SUD No SUD SUD No SUD SUD No SUD SUD No SUD

n =4280 n = 8194 n =2930 n = 5565 n =1527 n = 2940 n =558 n = 1197

On MPH, n (%) 3146 (74%) 5888 (72%) 1587 (54%) 2762 (50%) 739 (48%) 1 231 (42%) 249 (45%) 445 (37%)
Prescribed dose known n (%) 2659 (85%) 5400 (92%) 1400 (88%) 2610 (94%) 657 (89%) 1169 (95%) 211 (85%) 4196 (94%)
Mean daily dose in mg (sd) 67.3 (44.6) 53.9 (30.9) 76.6 (51.9) 59.4 (36.8) 87.0 (64.1) 60.7 (38.3) 84.8 (59.2) 60.7 (38.4)
Median (quartiles) 54 (36;90) 54 (36;72) 64 (40;92) 54 (36;72) 72 (46;108) 54 (36;72) 72 (40;108) 54 (36;72)
Min-max 5–440 4–324 4–420 4–620 9–590 10–452 9–360 10–320

Dose distribution, %
r 54 mg 54.2 69.1 45.1 61.4 40.3 59.8 42.2 58.5
55–72 mg 16.8 14.1 17.8 18.0 15.2 17.5 15.2 18.9
73–180 26.7 16.2 33.1 19.5 37.1 21.6 34.1 21.5
181–360 2.2 0.6 3.8 1.0 6.7 1.0 8.5 1.2
4360 0.1 0.0 0.2 0.1 0.6 0.2 0.0 0.0

Formulations, %
ER/OROS 89.3 85.5 87.0 83.4 86.5 82.0 87.1 81.1
IR 3.9 6.9 4.2 6.7 4.9 7.8 5.2 7.0
ER/OROS + IR 6.8 7.6 8.8 9.8 8.7 10.2 7.6 11.9

MPH=Methylphenidate, SUD=Substance Use Disorder, OROS=Osmotic Controlled Release Oral Delivery, ER=Extended Release
Formulation, IR=Immediate Release Formulation.
a
After initial prescription of methylphenidate.

Table 3 Logistic regression model of methylphenidate doses exceeding 72 mg/day.

Day 365 Day 730

Dose 472 mg/day Dose 472 mg/day

Unadjusted Adjusteda Unadjusted Adjusteda

n % OR (95% C.I.) OR (95% C.I.) n % OR (95% C.I.) OR (95% C.I.)

Total 4010 26 1826 31

SUD
No 2610 21 ref =1 ref =1 1169 23 ref =1 ref =1
Yes 1400 37 2.28 (1.98–2.64) 2.12 (1.81–2.47) 657 44 2.72 (2.21–3.34) 2.65 (2.13–3.30)

SUD Subtypeb
AUD 473 29 1.56 (1.25–1.94) 1.49 (1.19–1.87) 208 37 2.00 (1.46–2.73) 2.01 (1.46–2.78)
DA 453 41 2.69 (2.18–3.32) 2.53 (2.03–3.15) 227 48 3.14 (2.34–4.21) 3.09 (2.28–4.20)
AUD + DA 474 42 2.77 (2.25–3.40) 2.53 (2.03–3.16) 222 48 3.10 (2.31–4.17) 2.97 (2.16–4.09)
SU 500 47 3.48 (2.85–4.25) 3.08 (2.49–3.81) 256 53 3.79 (2.86–5.02) 3.63 (2.69–4.91)

MPH=Methylphenidate, SUD =Substance Use Disorder, AUD=Alcohol Use Disorder, DA=Drug Abuse, SU=Stimulant Use Disorder (Ever
diagnose of F15 304E, 304,60 = Mental and behavioural disorders due to psychoactive stimulant use).
a
Adjusted for sex, age, year of initial prescription, and psychiatric comorbidity.
b
Diagnosis of /Medication for.

Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
Fig. 2 Mean methylphenidate doses over time in individuals
with SUD compared to individuals with ADHD only. SUD =Sub-
stance use disorder, SUD =Individuals with comorbid Substance
use disorder who have been prescribed methylphenidate, No
SUD=Individuals with ADHD only who have been prescribed
methylphenidate.
observational nature of the study the investigators lacked
control over how unknown potentially confounding factors
were distributed across the two groups. Future studies
should explore the need for higher doses due to liver
enzyme induction following cigarette smoking, coexisting
psychopharmacological treatment or somatic disorders. The
study design does not allow for differentiating between the
quantity of medication prescribed and received, and the
amount of medication actually consumed. Thus the
observed finding of higher methylphenidate doses in indivi-
duals with ADHD and comorbid SUD might also to some
extent be explained by diversion, a phenomenon that may
be more prevalent in certain populations (Cassidy et al.,
2015). Studies targeting the extent of non-medical use of
stimulants (Kaye and Darke, 2012), in “high-risk” popula-
tions such as individuals with ADHD and comorbid SUD is
limited (Wilens et al., 2008) and this should be an important
focus for future research. Also, given that treatment with
methylphenidate, a schedule II classed medication (Con-
trolled Substance Act, FDA) is controlled (Heal et al., 2009,
Khan, 1979) and treatment guidelines often recommend
abstinence from abused substances prior to and during such
pharmacological treatment (NICE 2008, CADDRA) individuals
with ADHD and comorbid SUD might therefore be more
closely monitored (Heal et al., 2009). The proportionally
higher adherence to treatment among patients with SUD
might reflect the fact that these individuals, in order to
prevent abuse and medication diversion, receive more
intense psychosocial interventions and/or monitoring.
In conclusion, individuals with ADHD and comorbid SUD
were prescribed significantly higher methylphenidate doses
than those with ADHD only. Across the longitudinal follow-
up, mean prescribed doses stabilized over time in both
groups and the results do not lend support to continuously
increasing tolerance. Putative factors contributing to such
dosing differences need to be tested using prospective
designs. A clearer understanding of the natural long-term
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
7
course of stimulant medication and development of methyl-
phenidate doses over time should increase the evidence
base for stimulant pharmacotherapy among individuals with
combined ADHD/SUD.
Declaration of interest
The authors state no conflicts of interest.
Role of the funding source
C Skoglund had financial support from the Regional Agree-
ment on Medical Training and Clinical Research (K1426-
2011; 20120334) between the Stockholm County Council and
Karolinska Institutet, the Swedish Research Council (2013-
2280; 2012-2607), Swedish Initiative for Research on Micro-
data in the Social and Medical Sciences (SIMSAM) framework
(Grant no. 340-2013-5867), and National Institute of Mental
Health (NIMH) (Grant no. 1R01MH102221). H Larsson has
served as a speaker for Eli-Lilly and has received a research
grant from Shire; both outside the submitted work.
Contributors
C Skoglund is the lead author of the manuscript and affirms that the
manuscript is an honest, accurate, and transparent account of the
study being reported and that no important aspects of the study
have been omitted. C Skoglund and J Franck conceived and
designed the study. L Brandt performed the analyses and, with H
Larsson, assisted in the study design. C Skoglund performed the
search and drafted the report, which was revised by B D’Onofrio. All
authors had full access to the data in the study and take
responsibility for the integrity of the data and the accuracy of
the data analysis.
Conflicts of interests
The funders of the study had no role in the design or
conduct of the study, data collection, management, analysis
or interpretation, or in the preparation, review or approval
of the report. C Skoglund and L Brandt had full access to all
data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis. There were
no financial or other conflicts of interest among the other
authors. The lead author assumes responsibility for the
integrity of the data and the accuracy of the data analysis.
Acknowledgements
C Skoglund had financial support from the Regional Agreement on
Medical Training and Clinical Research (K1426-2011; 20120334)
between the Stockholm County Council and Karolinska Institutet,
the Swedish Research Council (2013-2280; 2012-2607), Swedish
Initiative for Research on Microdata in the Social and Medical
Sciences (SIMSAM) framework (Grant no. 340-2013-5867), and
National Institute of Mental Health (NIMH) (Grant no.
1R01MH102221).
8 C. Skoglund et al.
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Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance
use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435