British Journal of Clinical DOI:10.1111/bcp.

12045

Pharmacology

Correspondence
Pharmacological and clinical Dr Joan Trujols, Unitat de Conductes
Addictives, Servei de Psiquiatria, Hospital
de la Santa Creu i Sant Pau, Sant Antoni
dilemmas of prescribing in Maria Claret 167, 08025 Barcelona, Spain.
Tel.: +349 3553 7665
Fax: +349 3553 7666
co-morbid adult E-mail: jtrujols@santpau.cat
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attention-deficit/hyperactivity Keywords
addiction, adult
attention-deficit/hyperactivity disorder,

disorder and addiction atomoxetine, clinical practice, stimulants,

substance use disorders
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Received
Jos Prez de los Cobos,1 Nria Siol,1 Vctor Prez1,2 & 13 June 2012
Joan Trujols1,2 Accepted
20 November 2012
1
Unitat de Conductes Addictives, Servei de Psiquiatria, Hospital de la Santa Creu i Sant Pau, Institut Accepted Article
dInvestigaci Biomdica Sant Pau (IIB Sant Pau), Barcelona and 2Centro de Investigacin Biomdica Published Online
en Red de Salud Mental (CIBERSAM), Madrid, Spain 7 December 2012

The present article reviews whether available efficacy and safety data support the pharmacological treatment of adult
attention-deficit/hyperactivity disorder (ADHD) in patients with concurrent substance use disorders (SUD). Arguments for and against
treating adult ADHD with active SUD are discussed. Findings from 19 large open studies and controlled clinical trials show that the use
of atomoxetine or extended-release methylphenidate formulations, together with psychological therapy, yield promising though
inconclusive results about short term efficacy of these drugs in the treatment of adult ADHD in patients with SUD and no other severe
mental disorders. However, the efficacy of these drugs is scant or lacking for treating concurrent SUD. No serious safety issues have
been associated with these drugs in patients with co-morbid SUD-ADHD, given their low risk of abuse and favourable side effect and
drugdrug interaction profile. The decision to treat adult ADHD in the context of active SUD depends on various factors, some directly
related to SUD-ADHD co-morbidity (e.g. degree of diagnostic uncertainty for ADHD) and other factors related to the clinical expertise of
the medical staff and availability of adequate resources (e.g. the means to monitor compliance with pharmacological treatment). Our
recommendation is that clinical decisions be individualized and based on a careful analysis of the advantages and disadvantages of
pharmacological treatment for ADHD on a case-by-case basis in the context of active SUD.

Introduction According to the aforementioned systematic review,

The prevalence of adult attention-deficit/hyperactivity dis-
order (ADHD) in patients with substance use disorder
(SUD) is high. According to a recent systematic review [1],
the prevalence rate was 23.3% (95% CI 17.7%, 30.1%),
although prevalence varies depending on the psychoac-
tive substances involved and the diagnostic instrument.
Given the close bidirectional relationship between both
disorders, it seems highly improbable that the elevated
co-morbidity between adult ADHD and SUD is due to
chance alone. Some authors have even suggested that
SUD and ADHD could be different aspects of the same
overarching condition [2] or that the same endopheno-
type (i.e. impulsivity) may underlie both disorders [3].
approximately one-fifth of patients at SUD treatment
centres may also require drug therapy for ADHD, the
primary treatment for adult ADHD [4].
Pharmacological treatment of adult ADHD in patients
with SUD presents numerous clinical problems for clini-
cians. Although various drugs have proven effective in
the treatment of adult ADHD in patients who do not
suffer from SUD [5, 6], it is unclear whether these drugs
are also safe and effective in co-morbid SUD-ADHD. As a
result, clinicians are faced with an important clinical
dilemma related to the uncertainties surrounding the use
of these medications in patients with co-morbid SUD-
ADHD. It is not clear whether pharmacological treatment
for adult ADHD should be administered in patients with

2012 The Authors Br J Clin Pharmacol / 77:2 / 337356 / 337

British Journal of Clinical Pharmacology 2012 The British Pharmacological Society
 J. Prez de los Cobos et al.
co-morbid SUD. In the present review, we evaluate
the available evidence to determine whether there is
sufficient evidence to support pharmacological treatment
in these cases. We have reviewed the relevant clinical
and laboratory studies of adults with SUD to evaluate
the efficacy and/or safety of the drugs used to treat
ADHD.
A second dilemma confronting clinicians is the advis-
ability of administering pharmacological treatment for
adult ADHD in active substance abusers. Given that the
symptoms of both disorders tend to overlap each other,
correctly diagnosing ADHD in such cases is extremely chal-
lenging [7, 8]. In this review, we present the arguments for
and against treating adult ADHD in patients with active
SUD and we review the relevant literature related to these
arguments. We have structured our discussion to follow
the same steps carried out in our clinical decision-making
process. Finally, we give our recommendations based on
the information presented here as well as our own clinical
experience.
This article, authored by a group of clinician-scientists
with more than 10 years of clinical experience in the
treatment of severe addictions and/or personality disor-
ders, was written with a practical purpose: to provide a
decision making framework for clinical practice at centres
that specialize in treating adult SUD. Consequently, the
medical literature on childhood or adolescent ADHD is
only reviewed when necessary (i.e. when the available
information about that particular aspect of adult ADHD is
scant). It is important to keep in mind that the present
article is not a review of the risk of developing SUD.
Rather, the focus is on the risks of exacerbating SUD and
the potential for misuse/abuse of the drugs prescribed to
treat adult ADHD. In order to identify relevant studies and
literature reviews, we used the PubMed interface to
search MEDLINE (from inception up to March 2012). A
comprehensive search strategy, favouring sensitivity over
specificity, was performed using different combinations
of SUD-specific (e.g. substance abuse, drug dependence,
alcoholism, cannabis, cocaine, heroin, nicotine), ADHD-
specific (e.g. attention deficit hyperactivity disorder, atten-
tion deficit disorders, attention deficit disorder with
hyperactivity) and treatment-specific (e.g. amphetamine,
atomoxetine, bupropion, methylphenidate, modafinil,
pemoline) free-text and MeSH terms. Details on the full
search strategy are available from the corresponding
author upon request. Reference lists of relevant high
quality literature reviews were also reviewed to identify
additional pertinent studies.
In short, in the present review we evaluate two impor-
tant dilemmas related to drug safety, efficacy and interac-
tions that clinicians face when treating patients with
co-morbid SUD-ADHD: (i) Should adult ADHD be treated
pharmacologically in the context of an addiction? and (ii)
Must we wait until SUD is under control before initiating
pharmacological treatment of adult ADHD?
338 / 77:2 / Br J Clin Pharmacol
Should adult ADHD be treated
pharmacologically in the context of
an addiction?
Numerous clinical trials have found that pharmacological
treatment of ADHD is safe and effective for adults without
co-morbid SUD. However, because patients with SUD were
excluded from these trials, the results may not be general-
izable to the patient group addressed in this current
review. Consequently, our first aim is to determine if phar-
macological treatment of adult ADHD is safe and effective
in patients with concurrent SUD-ADHD. Secondly, in
patients with concurrent disorders, we must consider the
possibility that the drugs used to treat one disorder could
also affect the second disorder.It is important to determine
if there is any impact, and if so, whether that impact is
positive, negative or neutral. In other words, what are the
possible repercussions of pharmacological treatment for
ADHD on SUD?
Efficacy of pharmacological treatment for
ADHD on adults with SUD-ADHD: Overview
with an emphasis on the repercussions on the
addictive disorder
In the mid-1980s, a not inconsiderable number of case
reports were published on the treatment of adult ADHD in
patients with SUD (primarily cocaine dependence,
although a few cases of alcohol dependence were also
reported) treated with pemoline [9, 10] or bromocriptine
[11, 12]. Later, various open studies [1320] reported posi-
tive findings (see Table 1) regarding the clinical utility of
several different drugs (stimulants and some non-
stimulants) in patients with this dual disorder.These results
then led to the launch of several controlled clinical trials
[2131] (see Table 2).
Alcohol dependence and ADHD Only one controlled study
has been carried out in patients with alcohol dependence
and ADHD [26]. The 12 week study included 147 patients
(all with a diagnosis of alcohol abuse or dependence)
assigned to treatment with atomoxetine or placebo. Sub-
jects were required to abstain from alcohol in the 4 days
prior to the start of the study. Patients in the atomoxetine
treatment group showed significantly better improvement
in ADHD than the placebo group. Although no significant
differences between groups were observed regarding
time to initial relapse to heavy drinking, the atomoxetine
treatment group presented a significantly lower rate of
cumulative heavy drinking days. When responders to ato-
moxetine were compared with non-responders, no signifi-
cant differences were observed in the variables related to
alcohol use. Although various adverse events (e.g. nausea,
dry mouth) were observed more frequently in the treat-
ment group, this finding did not yield any significant dif-
ferences between groups in the discontinuation rate due
 Table 1
Uncontrolled clinical studies (with n 10 subjects) of stimulants and non-stimulants in adults with attention-deficit hyperactivity disorder and substance use disorder

First author Age (years) Co-morbid Study design, Medication and

(year) (SD) and male substance use setting and mean maintenance Concurrent
[Reference] n proportion disorder duration dose and/or range treatment Retention Main outcomes Adverse events Comments

Levin (1998) 12 34 (1.4) Cocaine Open; MPH SR Relapse prevention 66.7% ADHD: Significant reduction The most common AEs Psychiatric co-morbidity
[13] 60% dependence out-patient 68 mg day-1 in ADHD symptoms. were dry mouth, was common. Few
12 weeks 4080 mg day-1 SUD: Drug use severity, increased heart rate, medication doses were
cocaine craving and jitteriness and agitation. missed due to lack of
cocaine use (both No patient was attendance (91%
self-reported and discontinued due to AEs compliance with clinical
confirmed by urinalyses) appointments)
decreased significantly
Castaneda 19 36.6 (10.4) Cocaine Open; FLX 20 mg day-1 Medication-free patients 88.9% ADHD: 12 patients (63.2%) AEs were rare and mild. Stable patients in full or
(1999) 89.5% dependence out-patient BPR 200 mg day-1 (with the exception of were kept on a fully No evidence of any partial remission from
[14] 1 year PML 37.575 mg two bipolar patients effective single treatment abusive use of any cocaine dependence.
day-1 maintained on valproic regimen (suppression of stimulant medication Duration of remission
acid) almost 80% of the initial prior to ADHD treatment
MPH ER 40120 mg
ADHD symptoms) for 36 to ranged from 6 to 26
day-1
52 weeks (31.6% on MPH months (mean = 13.9).
d-AMP ER 60 mg day-1
ER). Most patients had at
m-AMP ER 15 mg day-1 SUD: Two patients (10.5%) least one associated
Progressive introduction had two 1 day cocaine psychiatric diagnosis.
(in the order listed) slips each. Two other Private practice study
and discontinuation patients (10.5%) had a
of ineffective treatment full-blown relapse
Upadhyaya 10 34.5 (5.7) Alcohol abuse or Open; VLFX No other psychotropic 33.3% ADHD: Significant One patient (10%) Exclusion criteria included

Adult ADHD and addiction

(2001) [15] 40% dependence out-patient Max = 300 mg day-1 medication. Supportive improvement in ADHD dropped out because of current Axis I diagnosis
(100%); 12 weeks psychotherapy. Possible symptoms. AEs (headaches) after or lifetime schizophrenia
cocaine abuse additional participation SUD: Significant improvement week 3 diagnosis. Four patients
Br J Clin Pharmacol

or in Alcoholics in alcohol craving intensity, (40%) had a history of

dependence Anonymous and and a trend toward major depression
(20%) routine outpatient improvement in frequency
group and/or individual
therapy for alcohol
abuse
/ 77:2
/
339
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/ 77:2

J. Prez de los Cobos et al.

Table 1
/
Br J Clin Pharmacol

Continued

First author Age (years) Co-morbid Study design, Medication and

(year) (SD) and male substance use setting and mean maintenance Concurrent
[Reference] n proportion disorder duration dose and/or range treatment Retention Main outcomes Adverse events Comments

Somoza (2004) 41 36 Cocaine Open; MPH IR Cognitive- 70.7% ADHD: The sample as a MPH IR was well-tolerated Sample primarily composed
[16] 76% dependence out-patient Max = 60 mg day-1 behavioural therapy whole, as well as the by participants. No of crack-cocaine
10 weeks compliant and serious AEs and no dependent patients.
non-compliant subgroups, persistent unresolved Participants were
experienced significant AEs rated as moderate required to provide at
improvement in their or severe. Higher doses least one urine positive
ADHD symptoms. were not associated with for benzoylecgonine
SUD: Subjective efficacy greater number of AEs. (cocaine metabolite)
measures (both patient- One participant was during the 1 week
and clinician-rated) discontinued due to AEs screening period and to
suggested that patients (chest tightness, provide a negative urine
(the whole sample as well restlessness, and tingling sample on the day of
as the compliant and in arm). One patient study enrolment.
non-compliant subgroups) discharged for abusing Measures of treatment
evidenced statistically MPH IR compliance included
significant improvement. MPH plasma levels and
Urine results indicated that staff ratings of
only the compliant participants compliance
subgroup succeeded in (to be categorized as
maintaining low levels of compliant, participants
use were required to have
scored above the
median for both
indicators)
Levin (2009) 20 39.3 (6.8) Cocaine Open; ATX Cognitive- 25% ADHD: 50% response rate. Most patients tolerated the Patients with no additional
[17] 95% dependence out-patient 80100 mg day-1 behavioural therapy SUD: No significant decrease medication well. Two severe psychopathology,
12 weeks in cocaine use (determined participants (10%) were but actively using
by urine toxicology and discontinued from the cocaine. Good
self-report) medication component medication compliance
of treatment due to AEs (monitored by self-report
(a) chest pain and b) and riboflavin
nervousness, anxiety, fluorescence testing)
insomnia and fatigue,
respectively)
 Adler (2010) 18 36.8 (10.0) Drug and/or Open; ATX NR 27.8% ADHD: Improvement of No serious AEs. Headache Abstinence from all
[18] 83.3% alcohol residential Max = 120 mg day-1 investigator- and and abdominal substances for at least 2
dependence treatment participant-rated ADHD pain/cramps were the weeks prior to study
(mainly facility symptoms. most commonly entry (mean length of
poly-substance 10 weeks SUD: Reduction in the reported TEAEs. None of abstinence at baseline
users; 33.3% intensity, frequency, and the AEs resulted in was 14.1 [SD = 18.5]
of whom length of cravings discontinuation of weeks). Exclusion criteria
reporting treatment included lifetime
cocaine as diagnosisof bipolar
primary drug disorder, schizophrenia,
of use) or schizoaffective
disorder
Wilens (2010) 32 32.0 (8.5) Substance use Open; BPR SR Patients treated with 59.4% ADHD: 65.6% response rate. No serious AEs. No AEs Exclusion criteria included
[19] 81.3% disorders; out-patient Max = 400 mg day-1 naltrexone, SUD: No clinically significant related to interactions clinically unstable
mainly alcohol 6 weeks methadone or reductions in either with substances of psychiatric conditions
and drug nicotine self-reported substance use abuse. No clinically (e.g. unstable SUD) and
abuse or replacement or investigator-rated scores. meaningful changes in lifetime bipolar or
dependence therapy were ADHD x SUD: ADHD cardiovascular signs. psychotic disorders
(68.8%) admitted responders were more Four patients (12.5%)
likely to have improved withdrew due to AEs,
SUD at end point. SUD including elevated blood
responders were more pressure, exacerbation of
likely to have improved panic attacks and one
ADHD symptoms at case of significant rash
endpoint
McRae-Clark 14 33.9 (13.2) Past stimulant Open; MPH TS 1.82 (0.36) Exclusion criteria 85.7% ADHD: Significant Most frequent AEs were Current abuse or
(2011) [20] 42.9% misuse, abuse, out-patient mg h-1 included current improvements from localized skin reactions dependence on
or 8 weeks 1.12.2 treatment with baseline were found on at the site of patch substances other than
dependence mg h-1 a psychoactive ADHD symptoms. application. Eight caffeine or nicotine was
Daily wear medication SUD: All submitted urine patients (57.1%) not permitted
time: samples (Mean [SD] = 7.6 reported
9.05 [1.8]) were negative for mild-to-moderate
(1.43) h stimulants. Only one localized irritation,

Adult ADHD and addiction

participant (7.1%) reported pruritis, or rash. Two
use of oral stimulants at participants (14.3%)
week 6 were removed due to
Br J Clin Pharmacol

AEs (severe localized skin

irritation, and
re-emergence of
depressive symptoms,
respectively)

Response rate refers to the percent of participants meeting the standard response criterion for the primary outcome measure (e.g. CGI-I score < 3 [i.e. much to very much improved] or a 30% reduction in symptoms in ADHD rating
scales when comparing the last observation to baseline); ADHD, Attention-deficit hyperactivity disorder; AE, Adverse event; ATX, Atomoxetine; BPR, Bupropion; d-AMP, Dexamphetamine; ER, Extended release; FLX, Fluoxetine; IR, Immediate
/ 77:2

release; m-AMP, Methamphetamine; MPH, Methylphenidate; NR, Not reported; PML, Pemoline; SR, Sustained release; SUD, Substance use disorder; TEAE, Treatment-emergent adverse effect; TS, Transdermal system; VLFX, Venlafaxine.
/
341
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/ 77:2

J. Prez de los Cobos et al.

/

Table 2
Br J Clin Pharmacol

Controlled clinical studies of stimulants and non-stimulants in adults with attention-deficit hyperactivity disorder and substance use disorder

Medication
and mean
First author Age (years) Co-morbid Study design, maintenance
(year) (SD) and male substance use setting and dose and/or Concurrent
[Reference] n proportion disorder duration range treatment Retention Main outcomes Adverse events Comments

Levin (2002) 11 30.7 (5.2) Cocaine dependence Single-blind; BPR Relapse 91.0% ADHD: Significant reduction of BPR was well-tolerated. The The MPH SR group served as
[21] 100% out-patient 250400 mg prevention ADHD symptoms no most frequently reported a historical control group
12 weeks day-1 significant differences AEs were agitation, dry (patients were not
between BPR and MPH SR. mouth, insomnia, randomized to either BPR
SUD: Significant reduction of constipation, and dizziness or MPH SR). Most patients
cocaine craving between had at least one current
baseline and the last 2 study Axis I diagnosis (mainly
weeks. Significant reduction alcohol or marijuana abuse
of cocaine use between the or dependence)
4 weeks before study entry
and the last 4 weeks of
study. No significant
differences between BPR and
MPH SR for cocaine craving
or use
Schubiner 48 37.1 (6.6) Cocaine dependence Double-blind, MPH Cognitive- MPH: 45% ADHD: Significant differences Occurrence of insomnia or High rate of Axis I
(2002) [22] 90% placebo-controlled, 78.8 (19.4) behavioural Placebo: 58% between groups on trouble sleeping was higher co-morbidity (mainly
parallel-group; Max = 90 mg therapy physician- and self-rated in the MPH group. No affective and anxiety
out-patient day-1 efficacy indexes. participants required disorders). Compliance
13 weeks SUD: No group differences in discontinuation of MPH (measured by self-report)
proportion of days of because of AEs was high. The sample was
reported cocaine use, stratified by gender. No
percentage of group differences in the
cocaine-negative urine proportion of participants
samples, duration of guessing their study
continuous abstinence, and medication correctly
craving
Carpentier 25 31.9 (5.8) Drug and/or alcohol Double-blind, MPH No concurrent 76% ADHD: 36% response rate MPH group showed Abstinence from all
(2005) 88.0% dependence placebo-controlled, Max = 45 mg use of any (Placebo: 20%), NS. significantly more AEs than substances for at least 3
[23] (primary cross-over; day-1 other SUD: NR (participants had to patients randomized to weeks prior to study entry.
substances of use: in-patient medication in remain abstinent for the placebo High psychiatry
cocaine [32%] and 8 weeks most cases total duration of the study) co-morbidity rate
alcohol [28%])
 Levin (2006) 98 39.0 (7.3) Opioid dependence Double-blind, MPH SR Medication and MPH SR: ADHD: 34% (MPH SR) and The medications were Exclusion criteria included
[24] 57.1% and cocaine placebo-controlled, 4080 mg treatment as 65.6% 49% (BPR SR) response rates well-tolerated. No group current psychiatric
dependence or parallel-group; day-1 usual in a BPR SR: (Placebo: 46%), NS. differences were observed disorders (other than
abuse out-patient BPR SR methadone 69.7% SUD: No significant differences with respect to AEs. The ADHD and SUD) and
12 weeks 200400 mg programme; placebo: across the groups in any most frequently reported physiological dependence
day-1 cognitive- 75.8% substance use outcome AEs were fatigue (Placebo, on either sedatives or
behavioural 9%) and increased alcohol. Compliance
therapy sweating (MPH SR, 6% (measured by self-report
and BPR SR, 9%). No and by riboflavin
evidence of abuse fluorescence testing) was
good and did not differ
across groups
Levin (2007) 106 37.0 (6.5) Cocaine Double-blind, MPH SR Cognitive- MPH SR: ADHD: 47.2% response rate No group differences were Exclusion criteria included
[25] 83.0% dependence placebo-controlled, 4060 mg behavioural 43.4% (placebo: 54.7%), NS. observed with respect to current psychiatric
parallel-group; day-1 therapy placebo: SUD: Approximately 70% of AEs. Only two patients disorders (other than
out-patient 45.3% the weeks were were discontinued because ADHD and SUD) and
14 weeks cocaine-positive. 17 patients of AEs (one in the MPH SR physiological dependence
(16%) achieved 2 group due to persistent on opioids, sedatives or
consecutive weeks of insomnia). Five participants alcohol. Compliance
abstinence; NS. Both groups had their doses lowered (measured by self-report
significantly reduced their (four in the MPH SR group and by riboflavin
craving over time; NS. The due to rash, insomnia, fluorescence testing) was
MPH SR group had a lower depressed mood, and good and did not differ
likelihood of cocaine use clenched jaw, respectively) between groups
over time.
ADHD x SUD: MPH
SR-responders (based on a
semi-structured clinical
interview) were more likely
to have a reduction in
cocaine use compared to
non-responders
Wilens 147 34.6 (10.0) Alcohol abuse or Double-blind, ATX None (outside ATX: 44.4% ADHD: Primary and secondary No serious AEs or specific Patients had to be abstinent
(2008) 85.0% dependence placebo-controlled, 89.9 (17.6) of 12-step Placebo: 64% measures of ADHD drug-drug reactions related from alcohol at least 4
[26] parallel-group; mg day-1 programmes) symptoms were significantly to current alcohol use. days (maximum 30 days)
out-patient Max = 100 mg improved in the ATX group Discontinuation rates due before randomization.

Adult ADHD and addiction

12 weeks day-1 compared with placebo. to AEs were low in both Exclusion criteria included
SUD: Time to initial relapse to groups and not diagnosis of current bipolar
heavy drinking showed no significantly different. AEs disorder, major depressive
Br J Clin Pharmacol

difference between groups. significantly more prevalent disorder, or psychosis.

ATX-treated patients had a
significantly lower rate of
cumulative heavy drinking
days.
ADHD x SUD: No statistically
significant differences
between ATX responders and
/ 77:2
in ATX-treated patients
were nausea, dry mouth,
decreased appetite,
dizziness, fatigue,
constipation, urinary
hesitation, hot flush, and
paraesthesia. Pulse, blood
History of non-alcohol SUD
did not preclude
participation provided that
patients were not actively
abusing other substances.
Psychotherapy,
pharmacological, or other

non-responders on any pressure, and QTcF change interventions for SUD

alcohol use variable from baseline (other than 12-step
measurements were similar programmes) were not
between groups permitted
/
343
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/ 77:2

Table 2
Continued

J. Prez de los Cobos et al.

/
Br J Clin Pharmacol

Medication
and mean
First author Age (years) Co-morbid Study design, maintenance
(year) (SD) and male substance use setting and dose and/or Concurrent
[Reference] n proportion disorder duration range treatment Retention Main outcomes Adverse events Comments

Konstenius 24 37.4 (9.9) Amphetamine Double-blind, OROS MPH Skills training OROS MPH: ADHD: Significant reduction of Most AEs were mild in Exclusion criteria included
(2010) [27] 75% dependence placebo-controlled, 72 mg day-1 programme 59% ADHD symptoms in both severity and reversible.current or past diagnosis of
parallel-group; Placebo: 84% groups; NS. Most commonly reported any other substance
out-patient SUD: No significant differences AEs were headache and dependence except
13 weeks between groups in AMP use nausea. Only one severe nicotine, and history of any
(self-report and urinalysis), AE (blurred vision, which
major psychiatric disorder
craving for AMP, time to disappeared with dose or any psychiatric condition
relapse or cumulative reduction) occurred in one
requiring medication. All
abstinence duration participant patients were required to
stay abstinent from all
psychoactive substances
(minimum of 4 weeks)
before entering the trial
McRae-Clark 38 29.9 (11.5) Marijuana Double-blind, ATX Motivational ATX: 47.4% ADHD: Participants treated All ATX-treated participants Exclusion criteria included
(2010) [28] 76.3% dependence placebo-controlled, Max = 100 mg interviewing Placebo: 36.8% with ATX showed greater experienced at least one dependence on any other
parallel-group; day-1 improvement on the CGI-I AE compared with 84% of substance (with the
out-patient scale than participants participants randomized to exception of caffeine or
12 weeks randomized to placebo. No placebo; NS. The risk of nicotine), history of
treatment group differences gastrointestinal AEs was psychotic disorder, current
on other ADHD rating scales. 2.25 times higher for major depression, and
SUD: No statistically significant ATX-treated patients current treatment with
differences between psychoactive medication
treatment groups in
marijuana use outcomes
Winhusen 255 37.8 (10.0) Nicotine dependence Double-blind, OROS MPH Nicotine OROS MPH: ADHD: 71% response rate No participant discontinued Exclusion criteria included
(2010) [29] 56.5% placebo-controlled, Max = 72 mg replacement 84.3% (placebo: 44%), statistically due to an AE. TEAEs current non-nicotine SUD,
parallel-group; day-1 therapy and Placebo: 84.4% significant difference. reported at significantly current major depression,
out-patient smoking SUD: No significant difference higher rates in the OROS current anxiety disorder
11 weeks cessation between treatment groups in MPH group included (except specific phobias),
counselling prolonged abstinence or dyspepsia, decreased antisocial personality
point-prevalence abstinence appetite, heart rate disorder, lifetime diagnoses
rates. increase, and palpitations. of bipolar disorder or
ADHD x SUD: No significant Tolerability for treatment psychosis, and positive
responder x treatment and the nicotine patch did urine screen for an illicit
interaction effects for not differ between groups drug. Medication
prolonged abstinence and adherence was high and
point prevalence abstinence did not differ significantly
between treatment groups
 Kollins (2011) 17 35.1 (10.3) History of SUD Double-blind, LDX NR History of SUD: ADHD: 65% response rate LDX was generally well Exploratory, post hoc analysis
[30] 54.3% (abuse of alcohol, placebo-controlled, 30, 50, or 83.3% (without a history of SUD: tolerated. Two participants on data from a forced dose
marijuana, m-AMP, parallel-group; 70 mg day-1 No history of 59%), NS (11.8%) with a history of titration study (n = 420).
or opioids; out-patient SUD: 82.9% SUD discontinued due to Exclusion criteria included a
dependence on 4 weeks psychiatric TEAEs. TEAE current co-morbid Axis I or
alcohol, AMP, or profile of participants with II diagnosis, a positive
m-AMP) a history of SUD was urinalysis, and SUD
similar to that of (excluding nicotine) within
participants with no history the past 6 months. No
of SUD patient with a history of
SUD was randomly
assigned to the placebo
group (n = 62)
Kollins 32 31.4 (8.7) Nicotine dependence Double-blind, LDX Nicotine LDX: 82.4% ADHD: Significant reductions in LDX was generally well Exclusion criteria included the
(in press) 62.5% placebo-controlled, 70 mg day-1 replacement Placebo: 93.3% self-reported and tolerated with respect to presence of any other
[31] parallel-group; therapy clinician-rated ADHD AEs and cardiovascular psychiatric condition and
out-patient symptoms compared with functioning. One use of psychoactive
6 weeks placebo. participant (5.9%) in the medication or illegal drugs
SUD: No effects compared with LDX group was
placebo on rates of discontinued because of a
continuous abstinence severe AE (marked anxiety)
(verified by self-report and possibly related to study
CO levels) drug. No significant
differences between
groups in cardiovascular

Adult ADHD and addiction

function.

Response rate refers to the percent of participants meeting the standard response criterion for the primary outcome measure (e.g. CGI-I score < 3 [i.e. much to very much improved] or a 30% reduction in symptoms in ADHD rating
Br J Clin Pharmacol

scales when comparing the last observation to baseline). ADHD, Attention-deficit hyperactivity disorder; AE, Adverse event; AMP, Amphetamine; ATX, Atomoxetine; BPR, Bupropion; LDX, Lisdexamfetamine dimesylate; m-AMP,
Methamphetamine; MPH, Methylphenidate; NR, Not reported; NS, No statistically significant difference between groups; OROS, Osmotic release oral system; QTcF, Corrected QT interval by Fridericias formula; SR, Sustained release; SUD,
Substance use disorder; TEAE, Treatment-emergent adverse effect.
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345
 J. Prez de los Cobos et al.
to adverse events. No specific drugdrug reactions related
to current alcohol use were observed.
Amphetamine dependence and ADHD The only control-
led study performed to assess the efficacy of pharmaco-
logical treatment of adult ADHD in patients with
co-morbid amphetamine dependence [27] found no dif-
ferences between the treatment and placebo groups. Sub-
jects were assigned to treatment with osmotic-release oral
system (OROS) methylphenidate or placebo. Although
ADHD symptoms decreased in both groups, no significant
differences were observed in symptom improvement or
for any of variables related to the addictive disorder (e.g.
use, craving, time to relapse, cumulative abstinence dura-
tion). It should be noted that patients were required to
remain drug free (minimum of 4 weeks) to participate in
the trial. Although most patients reported adverse events
(e.g. headache, nausea), these were mild in severity and
reversible.
Cannabis dependence and ADHD In adults with ADHD,
cannabis is the most commonly abused illegal substance
[32]. However, only one controlled study has been carried
out to evaluate the efficacy of a pharmacological agent to
treat adult ADHD in cannabis-dependent patients [28]. In
that study, participants were assigned to treatment with
atomoxetine or placebo. Patients in the atomoxetine treat-
ment group had a greater improvement on the Clinical
Global Impression of Improvement (CGI-I) scale although
not on other ADHD rating scales. No significant between
group differences were observed in any of the marijuana
use outcomes. One noteworthy (though not statistically
significant) finding was the increased risk of gastrointesti-
nal adverse events, which were 2.25 times greater in the
atomoxetine treatment group vs. placebo.
Cocaine dependence and ADHD Three double-blind,
placebo-controlled trials have been carried out in patients
with this dual disorder, with contradictory results regard-
ing the efficacy of the various methylphenidate formula-
tions that were evaluated [22, 24, 25]. We discuss one of
these studies, in which opioids were the primary drugs of
abuse, in Opioid dependence and ADHD below.
The first clinical trial performed in adults with cocaine
dependence and ADHD evaluated the therapeutic effi-
cacy of methylphenidate [22]. The authors found that
methylphenidate was significantly better than placebo in
improving ADHD symptoms as measured by both
physician-rated and self-rated indexes. Nevertheless, no
significant differences were found on any of the variables
relative to cocaine-dependence (e.g. self-reported cocaine
use days, percentage of cocaine-negative urinalyses,
craving levels). Although insomnia or trouble sleeping
were significantly more common in the methylphenidate
group, none of the participants abandoned treatment due
to adverse events.
346 / 77:2 / Br J Clin Pharmacol
A second controlled trial in patients with this dual dis-
order evaluated the efficacy of sustained-release methyl-
phenidate vs. placebo [25]. The use of methylphenidate
did not significantly decrease ADHD symptoms vs.
placebo. Moreover, the placebo response (54.7%) was
remarkably strong. Although no significant between
group differences were found for most variables related to
the cocaine addiction (e.g. percentage of patients able to
remain abstinent for 2 consecutive weeks, craving levels),
the methylphenidate group did show a reduced likeli-
hood of cocaine use over time. Moreover, differences were
observed within the active treatment group between
responders and non-responders. Patients whose ADHD
symptoms improved after methylphenidate therapy were
more likely to reduce cocaine use than patients who
showed no improvement.
Nicotine dependence and ADHD According to one study
in young adults, the number of ADHD symptoms has a
linear relationship with the probability of being a regular
smoker [33]. Nevertheless, to date, only two controlled
studies have assessed whether ADHD medications
enhance response to smoking cessation treatment in
smokers with co-morbid ADHD [29, 31]. Concomitant nico-
tine replacement therapy was used in both of these
studies, which we describe below.
In the first of these studies [29], patients treated with
OROS methylphenidate were compared with a placebo
treated group. The active treatment group had a higher
response rate, defined as a 30% reduction in the
DSM-IV ADHD Rating Scale [34] and a 1-point or greater
reduction in Clinical Global Impression-Severity scale from
baseline measures to the final week of the study. Never-
theless, for other variables, including prolonged absti-
nence, point prevalence abstinence rates, and treatment
by responder interaction, no significant differences were
observed between the groups. It is important to note that
patients in the active treatment arm were more likely to
experience adverse events (e.g. dyspepsia, decreased
appetite) although this did not result in significant
differences between the groups in the discontinuation
rate due to adverse events. Likewise, no significant
between group differences were observed in nicotine
patch tolerability.
The second controlled study in patients with nicotine-
dependence and co-morbid ADHD [31] reported that lis-
dexamfetamine dimesylate (LDX) was significantly more
effective than placebo in reducing both self- and clinician-
reported ADHD symptoms. However, between-group dif-
ferences in continuous abstinence rates (verified by self
report and CO levels) and cardiovascular functioning were
not significant.
Opioid dependence and ADHD Only one randomized
clinical trial has been carried out to evaluate ADHD treat-
ment in patients with concomitant opioid dependence.

That trial involved 98 patients on methadone maintenance
treatment randomized to sustained release methylpheni-
date, sustained release bupropion or placebo [24]. None of
the active medications was found to be more effective
than placebo on any of the outcome variables related to
ADHD, opioid dependence, or concomitant cocaine
dependence. The strong clinical response to placebo was
noteworthy: on the self-rated Adult ADHD Rating Scale
(AARS) [35], 46% of participants in the placebo group
reported a large decrease in ADHD symptoms. No cases of
misuse of the methylphenidate or bupropion sustained
release preparations were observed, nor were any cases of
intensification of cocaine use reported in these two treat-
ment groups.
Safety and abuse liability of stimulant and
non-stimulant medications for ADHD in
patients with co-morbid SUD: Experimental
and laboratory findings
In addition to the data provided by controlled clinical trials,
additional data on the safety and abuse liability of some of
the medications used to treat adult ADHD have been
obtained through a few experimental studies involving
drug users.
Safety One study assessed the effects of intravenous
cocaine administration during treatment with sustained-
release methylphenidate (up to 60 mg day-1) in cocaine
dependent adult patients with ADHD [36]. Importantly, this
study found that the cardiovascular effects of cocaine
administration were not clinically significant in the study
group, thus suggesting that maintenance on sustained
release methylphenidate is safe in cocaine dependent
patients with ADHD.
Another study, in which patients were recruited
without regard to ADHD, evaluated the safety of immedi-
ate release methylphenidate (up to 90 mg day-1) in cocaine
dependent individuals receiving concurrent intravenous
cocaine [37]. The principal findings of that study can be
summarized as follows: (i) methylphenidate in combina-
tion with cocaine is well-tolerated, (ii) methylphenidate
does not significantly alter the pharmacokinetics of
cocaine, (iii) no clinically significant ECG findings were
observed with respect to interaction between the two sub-
stances and (iv) methylphenidate reduces some of the
positive subjective effects of cocaine.
Finally, another study examined the safety, tolerability
and subject-related effects of acute intranasal cocaine
administration during atomoxetine maintenance (up to
80 mg day-1) in cocaine dependent individuals [38]. Results
showed that atomoxetine attenuates the systolic pressure
increasing effects while enhancing the heart rate increas-
ing effects of cocaine, but otherwise has no behavioural
effects.The authors conclude that cocaine is well-tolerated
during atomoxetine maintenance.
Adult ADHD and addiction
Abuse liability Two separate studies reported that the
abuse liability of atomoxetine in drug users is scant and
notably lower than non-modified release preparations of
methylphenidate. The subjective effects of atomoxetine
(up to 90 mg day-1) and methylphenidate (up to 40 mg
day-1) were compared in recreational drug users with no
history (aside from nicotine) of drug or alcohol depend-
ence [39]. The authors concluded that atomoxetine does
not induce subjective effects that are similar to those elic-
ited by methylphenidate. Another study compared the
abuse liability of atomoxetine (45, 90, and 180 mg day-1),
methylphenidate (90 mg day-1), phentermine (60 mg
day-1), desipramine (100 and 200 mg day-1) and placebo in
subjects with a diagnosis of current stimulant abuse [40].
Findings revealed that participants liked methylphenidate
and phentermine significantly more than placebo, atom-
oxetine and desipramine. In contrast, none of the atomox-
etine doses were liked significantly more than placebo.
Mean liking scores for atomoxetine were similar to, or sig-
nificantly lower than, mean scores for desipramine.
Other studies have found that the abuse liability of
OROS methylphenidate in recreational drug users is much
lower than that of non-modified release methylphenidate.
In one randomized crossover study [41], participants
received single oral doses of placebo, methylphenidate
(60 mg) and OROS methylphenidate (108 mg). Findings
showed that the subjective effects of methylphenidate
and OROS methylphenidate differed significantly from
placebo. Even though the dose of OROS methylphenidate
was higher than the methylphenidate dose, abuse-related
subjective effects were consistently lower for OROS meth-
ylphenidate. A second study [42] evaluated the abuse-
related subjective effects of comparable doses of OROS
methylphenidate (54 mg and 108 mg) and methylpheni-
date (50 mg and 90 mg). In that study, only the lower
dose of OROS methylphenidate (54 mg) failed to produce
statistically significant differences when compared
with placebo. At comparable dose levels, OROS-
methylphenidate produced lower positive and stimulant
subjective effects than methylphenidate. Moreover, low
dose methylphenidate (50 mg) produced greater subjec-
tive effects than high dose OROS methylphenidate
(108 mg).
A recent study investigated the abuse liability of single
oral doses of 50, 100 and 150 mg of LDX in adults with a
current diagnosis of stimulant abuse [43]. Although no sig-
nificant difference in liking scores between non-modified
release 40 mg dexamphetamine and 150 mg LDX were
observed, liking scores for 100 mg LDX were significantly
lower than for 40 mg dexamphetamine.
The results of the studies reviewed in this subsection
strongly suggest that drugs used to treat adult ADHD can
be classified into three categories according to their abuse
liability, listed here from higher to lower abuse liability:
(i) non-modified release stimulants (e.g. immediate release
methylphenidate and dexamphetamine), (ii) extended
Br J Clin Pharmacol / 77:2 / 347
 J. Prez de los Cobos et al.
release or long acting stimulants (e.g. OROS-
methylphenidate, LDX) and (iii) non-stimulant agents (e.g.
atomoxetine).
Final considerations
The methodology and the results of the controlled trials
carried out in SUD patients with co-morbid adult ADHD
raise a number of practical issues, addressed below, that
should be taken into account by clinicians analyzing the
possible answers to the first dilemma.
First, it appears that although the various drugs (both
stimulants and non-stimulants) assessed in these studies
can improve ADHD in the short term, they are less effective
in ADHD patients with addictive disorders than in patients
without these co-morbid disorders. Two meta-analyses,
both of which concluded that methylphenidate appears to
be less efficacious in adult patients with co-morbid SUD,
support this conclusion [44, 45]. This lack of efficacy
appears to remain unchanged even when patients refrain
from using psychoactive substances (including the
primary dependence-related substance) [23]. It seems
unlikely that this lack of efficacy is due to poor adherence
to pharmacological treatment because treatment compli-
ance was high in the double-blind placebo clinical trials
that have investigated this issue [22, 24, 25, 29]. Moreover,
one open study did not find any association between dif-
ferences in treatment compliance and ADHD improve-
ment [16]. Consistent with this counterintuitive result, a
recent review concluded that the available evidence is
ambiguous in terms of whether differences in adherence
affect clinical outcomes in patients treated for adult ADHD
[46].
Second, these ADHD drugs appear to have little to no
efficacy in the treatment of co-morbid addictive disorders.
Although this lack of efficacy may be somewhat disap-
pointing, one positive aspect of note is that these ADHD
drugs do not appear to exacerbate addictive disorders.
None of the controlled clinical trials performed to date
have found any evidence of exacerbation, nor have any
cases of medication abuse or misuse been reported. Nev-
ertheless, it should be noted that a few rare cases of abuse/
misuse have been reported in uncontrolled clinical studies.
Third, ADHD medications seem to exert a strong
placebo effect on ADHD symptoms in patients with addic-
tive disorders. Some studies report placebo response rates
as high as 45%55% [24, 25, 29].The high placebo response
may be related to a non-specific effect of addiction treat-
ment on impulsivity and aggressiveness. Such an effect
probably lessens the severity of some clinical manifesta-
tions of ADHD. Another possible explanation is that
patients with addictions, and/or the clinicians who treat
them, have high expectations that medical treatment will
improve ADHD symptoms. In any case, this information
needs to be considered when interpreting the results dis-
cussed above, and to ensure adequate sample sizes in any
new controlled clinical trials.
348 / 77:2 / Br J Clin Pharmacol
Fourth, in the large majority of controlled studies
carried out to date, participants received some type of psy-
chosocial intervention (mainly cognitive behavioural
therapy). Consequently, clinicians must consider the
reported efficacy of these drugs, and even the placebo
response rates, in the context of concomitant psychosocial
treatment. However, it is important to note that the psy-
chological interventions in most of the studies were prima-
rily designed to treat the addictive disorder. This approach
is very different from the one taken in most clinical studies
designed to assess the efficacy of a specific drug in the
treatment of ADHD patients without co-morbid SUD. In
those studies, psychological interventions (when offered)
are performed to reduce ADHD symptoms.
Fifth, and last, none of the controlled clinical trials dis-
cussed here stratified participants by dependence severity
or by ADHD subtype. These variables may be important
according to a recent secondary analysis [47] of the data
collected in the original Winhusen et al. study [29]. In the
original study [29], OROS methylphenidate was not supe-
rior to placebo in improving response to smoking cessa-
tion treatment. However, the secondary analysis revealed
that ADHD subtypes present divergent smoking cessation
responses to OROS methylphenidate or placebo as a func-
tion of severity of nicotine dependence [47]. More specifi-
cally, the secondary analysis found: (i) a significant benefit
of OROS methylphenidate vs. placebo for the combined
(inattentive and hyperactive/impulsive) ADHD subtype
when nicotine dependence is high, (ii) a worse response to
active drug among smokers with the predominantly inat-
tentive subtype when nicotine dependence is high and (iii)
no added benefit of OROS methylphenidate regardless of
ADHD subtype when nicotine dependence is low.
Conclusion
Evidence from large open studies and controlled trials in
patients with SUD and co-morbid ADHD suggests that the
drugs typically used in the treatment of adult ADHD, par-
ticularly long acting or extended release preparations of
stimulants and the non-stimulant atomoxetine (all of
which are generally administered in conjunction with
diverse psychological interventions), offer promising
though not conclusive efficacy results in the short term
treatment of ADHD in patients with SUD but without other
severe mental disorders. Despite the lack of long term
studies, these drugs have an adequate tolerability profile in
adult patients with SUD and ADHD co-morbidity. However,
at the same time, the efficacy of these drugs is limited or
non-existent in SUD treatment. Nevertheless, the adequate
tolerability profile of long acting stimulant preparations
and atomoxetine in this group of patients, together with
their favourable drugdrug interaction profile, suggest
that these drugs are unlikely to raise any important safety
issues when used to treat patients with SUD-ADHD
co-morbidity.

Must we wait until SUD is under
control before initiating
pharmacological treatment
of adult ADHD?
The two possible responses to this question (i.e. yes or no)
could lead to clinically divergent scenarios. On one hand,
delaying ADHD treatment until SUD is controlled would
create ideal conditions for diagnosing and treating ADHD
because it would eliminate the interference from the SUD.
However, achieving satisfactory control of SUD is very dif-
ficult in severe cases, such as those often associated with
ADHD. Moreover, waiting until SUD is under control might
require an extended or even indefinite postponement in
starting ADHD treatment. On the other hand, we could opt
to treat the ADHD without waiting to control SUD. This
would improve the ADHD and might make it easier to
control the SUD. However, this plan requires that ADHD be
diagnosed and treated in a clinically complex context,
thereby increasing the probability of therapeutic failure.
Moreover, the reinforcing effect of the stimulants used to
treat ADHD increase the risk of SUD exacerbation.
In clinical practice, it is not possible to avoid making a
treatment decision.We must, inevitably, select one of these
two approaches to manage co-morbid SUD and ADHD
even though, as we discussed previously, conclusive results
regarding the efficacy of pharmacological treatment of
ADHD in patients with SUD are not available. However,
despite the lack of a definitive treatment approach, a thor-
ough understanding of the advantages and disadvantages
of pharmacological treatment of ADHD in patients with
active SUD might simplify the clinical decision making
process.The purpose of the present section of this review is
to assess the relevant aspects of this dilemma. However,
this analysis is limited almost exclusively to ADHD medica-
tions with the least abuse liability (i.e. extended release
stimulants and atomoxetine), which are precisely those
medications that are typically used to treat adult ADHD in
patients with SUD.
Arguments in favour of immediate treatment
of ADHD
ADHD treatment can help to control SUD better This
approach relies on the possibility that adult ADHD is a
causal factor for SUD. If this hypothesis is true, then phar-
macological management of ADHD would be an aetiologi-
cal treatment for SUD. Moreover, the drugs used to treat
ADHD might have a direct, positive effect, unmediated by
ADHD, on SUD.
Adult ADHD as a causal factor for SUD Before a decision
can be made to treat or not adult ADHD in order to control
SUD, it is essential to determine whether the persistence of
ADHD in adults is a causal factor of persistent SUD. To
assess fully whether adult ADHD contributes to SUD per-
sistence, we must first ascertain whether adult ADHD pro-
Adult ADHD and addiction
motes the lifetime incidence of SUD.To our knowledge, this
possible association has yet to be investigated. Most
studies that have been performed in this area have evalu-
ated the association between childhood or adolescent
ADHD and substance use or addiction during adolescence
or in young adults [4850].
ADHD as a causal factor in the development of
SUD At present, the available data on the role of child-
hood or adolescent ADHD as a causal factor for SUD is
contradictory.To evaluate this association, it would be nec-
essary to investigate whether childhood ADHD is an inde-
pendent predictor of SUD or if the pharmacological
treatment of childhood ADHD prevents the emergence of
SUD. However, in both of these scenarios, the presence or
not of conduct disorder must also be considered due to
the high co-morbidity between ADHD and conduct disor-
der [51] and because conduct disorder is one of the most
robust risk factors for SUD [48, 50, 52].
According to a recent series of meta-analyses, child-
hood ADHD is a predictor for SUD in young adults [49].
However, this finding must be considered in context. Most
of the studies included did not adjust for the presence of
conduct disorder. Moreover, findings from the two well-
designed studies that did adjust for conduct disorder were
contradictory. In one study, the association between child-
hood ADHD and SUD was found to persist into young
adulthood [53] while the other found that this association
was not maintained [54].
One meta-analytic review found that treatment of
ADHD with stimulants during childhood and adolescence
prevented the development of SUD [55]. However, once
again, findings were not adjusted for the presence of
conduct disorder. Several subsequent studies, in which the
results were adjusted for the presence of conduct disorder
(or antisocial personality disorder, the adult equivalent to
conduct disorder), have shown that the pharmacological
treatment of ADHD neither increases nor reduces the risk
of SUD in adults [5658].
If conduct disorder alone were a causal factor for SUD,
treating ADHD to control SUD would not be effective.
However, this line of reasoning may not apply to ADHD
patients who also suffer from conduct disorder. Substance
use in young adults with a history of childhood ADHD
alone (i.e. without conduct disorder) is less intense and
diverse than substance use in patients who had both
ADHD and conduct disorder in childhood [59].This finding
supports the hypothesis that childhood ADHD and
conduct disorder interact synergistically, leading to a par-
ticularly severe form of SUD [48].Two 5 week, double-blind
clinical trials found that methylphenidate reduces conduct
disorder in children with [60] and without ADHD [61].
However, it is clearly not possible to extrapolate results
obtained in patients with childhood ADHD and conduct
disorder to adults with ADHD and antisocial personality
disorder. That said, antisocial personality disorder is
Br J Clin Pharmacol / 77:2 / 349
 J. Prez de los Cobos et al.
probably a predictor for non-medical stimulant use during
treatment for adult ADHD.
Adult ADHD as a causal factor in persistent SUD It is
unclear whether ADHD contributes or not to the emer-
gence of SUD in young adulthood, although published
data support the hypothesis that adult ADHD contributes
to persistent SUD. Several transversal studies have
reported that patients with adult ADHD experience more
severe SUD than their counterparts without adult ADHD.
This difference (unadjusted for the presence of conduct
disorder) has been observed in studies in which patients
with co-morbid SUD-ADHD presented more substance use
disorders [62], more intense drug craving [63], greater
severity of substance use [64], and, importantly for SUD
persistence, a worse response to various addiction treat-
ments [65, 66]. In studies that did adjust for conduct disor-
der and other mental disorders, adult ADHD was
associated with earlier onset [67] and more persistent SUD
[68].
The clinical alterations that characterize adult ADHD
could contribute to SUD persistence through two non-
exclusive mechanisms. Awareness of these mechanisms
has important therapeutic implications for clinicians. The
first mechanism is related to alterations in attention [69]
and impulsivity [70], both of which favour persistent SUD.
In addition, ADHD is often associated with deficits in
executive functions [71, 72], and such dysfunctions have
also been considered to have an aetiological relation to
SUD [73]. The second mechanism by which adult ADHD
might contribute to SUD persistence is through the use of
substances of abuse to self-medicate ADHD [74]. This self-
medication hypothesis assumes that ADHD symptoms
improve when a specific substance is consumed. However,
this may not be true. A laboratory study of cocaine abusers
with ADHD found that acute administration of cocaine
worsened self-ratings for Able to concentrate, and Calm more than 75% of participants experienced clinically sig-
[36]. Several studies suggest that nicotine is used to self-
medicate ADHD. Indeed, for this reason, pharmacological
treatment of ADHD is considered crucial in smoking cessa-
tion treatments [75]. During abstinence from nicotine,
smokers with ADHD show worse performance on tasks
requiring attentional control and response inhibition
when compared with counterparts without ADHD [76]. In
addition, two double-blind crossover studies suggest that
a nicotine patch is more effective than a placebo patch in
improving the ability of smokers with ADHD to concen-
trate 812 h after interruption of nicotine consumption
[77, 78].
Utility of pharmacological treatment for ADHD to treat
SUD Adult ADHD has been linked to a dysregulation of
brain dopamine and norepinephrine systems [79], which
explains the therapeutic efficacy of drugs that act as cat-
echolaminergic agonists. Given that SUD has also consist-
ently been linked to dysregulation of the brain dopamine
350 / 77:2 / Br J Clin Pharmacol
system [80, 81], stimulants and other drugs that affect that
system might be effective in treating SUD regardless of
their impact on ADHD. The results discussed below show,
however, that despite this possible mechanism, drugs used
to treat ADHD have not, in general, proven effective in
treating SUD.
One meta-analysis reviewed a total of nine controlled
trials and concluded that stimulants are not effective in
treating cocaine dependence [82]. In that meta-analysis,
the authors evaluated two clinical trials in which patients
with adult ADHD were excluded and only one clinical trial
that specifically included ADHD. The remaining six trials
either did not evaluate ADHD or did not report whether
ADHD was evaluated or not. Two double-blind placebo-
controlled pilot trials found that modafinil improved
mnestic function in patients with methamphetamine
dependence without ADHD [83] or without other Axis I
psychiatric disorders (exclusion due to ADHD was not
specified) [84].
An 8 week, randomized, double-blind, clinical trial of
smokers without ADHD concluded that extended release
methylphenidate was not effective in treating nicotine
dependence [85]. In contrast, a double-blind, crossover
laboratory study [86] found that atomoxetine reduced
symptoms of nicotine abstinence in patients without
ADHD. Atomoxetine was also effective in treating nicotine
addiction in subjects who completed a 21 day, parallel,
double-blind, clinical trial in which patients with any other
Axis I psychiatric disorder were excluded (exclusion due to
ADHD was not specified) [87]. However, five of the nine
participants treated with atomoxetine in that study aban-
doned treatment due to the adverse events associated
with the drug. An 11 week, open label study of cannabis
dependent patients without co-morbid ADHD concluded
that atomoxetine should not be used to treat this addictive
disorder because efficacy was limited or non-existent and
nificant adverse gastrointestinal events [88].
Patient belief that pharmacological treatment of ADHD is
a priority In our clinical experience, the acceptability of a
diagnosis of ADHD is very high in young adults with SUD
and some even request treatment because they are con-
vinced that they suffer from ADHD. This attitude towards
an ADHD diagnosis contrasts with the low acceptability
often observed when a diagnosis of SUD is made. We
suspect that the high acceptability for ADHD diagnosis in
SUD patients may be related to the patients desire to
receive pharmacological interventions to treat his/her
problems, or it may reflect an intention to use stimulants
for non-medical purposes.
Patients who show a high acceptability for an ADHD
diagnosis sometimes assume that the disorder is the cause
of their history of disruptive behaviour and SUD. Such
patients may harbour the hope that pharmacological
treatment of their ADHD will also solve their other prob-

lems. Obviously, this expectation implies a high risk of
abandonment of SUD treatment if the request for pharma-
cological treatment of ADHD is not met quickly.
In patients who believe that pharmacological treat-
ment for ADHD is a priority and who show a strong interest
in receiving medical treatment for this disorder, we recom-
mend the following approach. First and foremost, deter-
mine if the patient fulfils diagnostic criteria for adult ADHD.
If the diagnosis is confirmed, or at least considered highly
probable, the next step is to redirect the patients expec-
tations towards realistic therapeutic objectives. To do this,
the patient should be informed of the following facts: (i)
remission of ADHD is not necessarily associated with SUD
remission because SUD does not have a single cause, (ii)
both ADHD and SUD require specific therapeutic interven-
tions, (iii) adult ADHD does not always respond well to
pharmacological treatment and (iv) treatment of SUD will
likely improve ADHD symptoms. Once the patients expec-
tations have been lowered, pharmacological treatment for
ADHD can be initiated under the close supervision of
nursing staff, as described in Risk of non-medical drug use.
Arguments against
Diagnostic uncertainty in adult ADHD Diagnosis of adult
ADHD requires that clinicians evaluate not only current
symptoms, but that they also retrospectively evaluate
symptoms that were present in the past (i.e. during child-
hood and adolescence).However, these clinical evaluations
are particularly difficult to perform in patients with active
SUD [7, 89].
Clinical evaluation of ADHD during adulthood in a
patient with SUD is difficult due to changes that occur in
attention, motor activity and/or impulsiveness [90] in the
context of substance intoxication or withdrawal. Given the
overlap between ADHD and SUD symptoms, it is essential
that clinicians be prepared to evaluate for ADHD when
patients interrupt their substance use, as occurs when they
are admitted to a detoxification unit. No definite criteria
are available to determine how long a patient should
abstain from substance use before an assessment of ADHD
can be performed. However, some experts assert that 14
weeks of abstinence is sufficient to allow current ADHD to
be assessed with a reasonable degree of diagnostic cer-
tainty [91]. The clinical evaluation should be performed by
an experienced clinician who is capable of deciding
whether the attention or impulsivity problems observed
are to be expected in a drug dependent patient who has
not used substances for 14 weeks, or whether such symp-
toms would be better explained by ADHD.
Substance abuse can hinder the retrospective evalua-
tion of childhood or adolescent ADHD. Firstly, ADHD can
emerge after age 7 years [92] while substance use can
appear in early adolescence, thus making it difficult to
determine retrospectively if the patient suffered ADHD
symptoms before starting to use psychoactive substances.
Moreover, mnestic difficulties related to substance use
Adult ADHD and addiction
probably reduce the validity of any assessment of past
ADHD [89]. Furthermore, the impact of SUD on relation-
ships with the family of origin reduces the likelihood of
having access to external informants capable of describing
patient functioning during the early stages of life.
Patients with SUD and ADHD during adulthood can be
divided into two groups: those with adult ADHD and those
that only present ADHD in the context of substance abuse
[11, 62]. In patients with adult ADHD, the onset of the dis-
order may have occurred before age 7 years (as required by
DSM-IV criteria for a diagnosis of ADHD), or after age 7
years, in which case the DSM-IV diagnosis is ADHD, not
otherwise specified [90]. However, such a distinction is not
clinically relevant in SUD patients because it does not dis-
criminate with regard to SUD prevalence and associated
problems [92, 93].
Risk of patients condition worsening
Risk of non-medical drug use Non-medical drug use can
involve abuse related to SUD, misuse to enhance perform-
ance of cognitive, athletic, sexual or other functions, and
diversion, usually to obtain the substance of abuse pre-
ferred by the patient. Obviously, patients with SUD are at a
particularly high risk of engaging in non-medical use of
ADHD medications. In some cases, several of the various
non-medical uses of stimulants described above are
observed in a single patient. To give just one example, a
male treated with extended release methylphenidate at
our clinic took the drug after dinner on evenings when he
planned to go out to bars/discotheques. He told us that he
used the drugs to avoid becoming sleepy and to increase
his sexual function and alcohol tolerance.
To minimize the risk of non-medical stimulant use,
pharmacological treatment of adult ADHD in SUD
patients usually involves drugs that have an abuse liability
that is considered either low (extended release stimu-
lants) or very low (atomoxetine) [39, 40]. Extended release
stimulants have been found to have a reinforcing effect in
some patients with a history of recreational use or abuse
of substances [94], even in cases where the proper route
of administration is used [41], and especially at elevated
dose levels [42, 43]. In our experience, the risk of non-
medical use of extended release stimulants can be
reduced considerably by administering the medication
under the close supervision of nursing care, as occurs with
other medications (e.g. methadone) in use at SUD treat-
ment centres.
Nursing supervision involves evaluating the patient
13 times per week to assess his/her state, administering
the dose scheduled for that day, providing the doses
planned for home use until the next nursing appointment,
and collecting a urine sample for laboratory analysis (i.e. to
check for the presence of substances of abuse and, if rel-
evant, methylphenidate). Urinary analysis permits detec-
tion of any changes in the pattern of substance use
and allows us to determine if the patient is not taking
Br J Clin Pharmacol / 77:2 / 351
 J. Prez de los Cobos et al.
methylphenidate due to diversion. The frequency of
nursing supervision can be progressively reduced if treat-
ment compliance is adequate. Nursing supervision should
be closer in patients that present a greater risk of non-
medical stimulant use. In our clinical experience, high risk
patients are those who request immediate treatment with
stimulants (see Patient belief that pharmacological treat-
ment of ADHD is a priority), those who report a prior history
of non-medical stimulant use, and patients who are
addicted to various substances or suffer from other mental
disorders in addition to co-morbid SUD-ADHD. To our
knowledge, no studies have been performed to identify
predictors for the non-medical use of stimulants in adults
with SUD.
The availability of drugs with a low or very low risk of
abuse, the high level of safety in terms of interactions
between these drugs and substances of abuse [37, 38], and
the clinical skills of professionals who work in SUD treat-
ment centres all suggest that the risk of non-medical drug
use is not a strong argument against treating ADHD with
uncontrolled SUD.
Risk of exacerbating other mental disorders A large
percentage of patients with adult ADHD present other
mental disorders in addition to SUD [95], some of which
have a bidirectional relationship with SUD (e.g. bipolar
disorder and eating disorders). As discussed in the previ-
ous subsection, the presence of such disorders can
increase the risk of non-medical stimulant use. In addi-
tion, the clinical manifestations of other mental disorders,
added to the co-morbidity of SUD-ADHD, can be exacer-
bated through the use of the drugs used to treat ADHD,
or can be confused with the side effects of these drugs.
For example, a patient with bipolar disorder could suffer
mania in response to stimulant administration [96] and
the manic state could worsen the SUD. Irritability, suicidal
thoughts, self-harm behaviours and behavioural changes
are characteristic symptoms of borderline personality dis-
order [90], yet they have also been reported as a side
effect of atomoxetine administration [97]. As a result, it
can be difficult to assess whether a decompensation of
borderline personality disorder has occurred in adults
with co-morbid SUD-ADHD who receive atomoxetine. In
addition to the complexities of these varied clinical situ-
ations, we must also consider the lack of data regarding
their management. Most clinical trials performed to
evaluate drugs used to treat ADHD in adults with SUD
exclude patients with other severe mental disorders (see
Efficacy of pharmacological treatment in ADHD on adults
with SUD-ADHD: Overview with an emphasis on the reper-
cussions on the addictive disorder). For all these reasons,
the risk of exacerbating other mental disorders that
have the potential for significant interactions with
the co-morbid conditions of SUD-ADHD is a strong argu-
ment against treating adult ADHD before SUD has been
controlled.
352 / 77:2 / Br J Clin Pharmacol
Conclusion and final
recommendation
The decision to treat or not treat ADHD in the context of
active substance abuse depends on numerous factors.
Among these, the most notable are the bidirectional rela-
tionship between SUD and ADHD (which can vary depend-
ing on the type of substance involved), the patients
opinion about the importance of ADHD in his/her particu-
lar case, the degree of diagnostic uncertainty for ADHD, the
risk of exacerbating SUD or other mental disorders by
treating the ADHD, the experience of the therapeutic team
in the management of SUD-ADHD co-morbidity, and the
ability to closely monitor the patients response to treat-
ment and adherence to pharmacological treatment.
Our recommendation is to individualize the treatment
decision required by this dilemma.This should be done on
a case-by-case basis in which the arguments for and
against immediate pharmacological treatment of ADHD
are carefully weighed. The results of such an assessment
will indicate when to initiate ADHD treatment and the
most appropriate choice of drug.
Competing Interests
All authors have completed the Unified Competing Inter-
est form at http://www.icmje.org/coi_disclosure.pdf (avail-
able on request from the corresponding author) and
declare no support from any organization for the submit-
ted work; no financial relationships with any organizations
that might have an interest in the submitted work in the
previous 3 years (except in the case of JP, who declares
having acted as a speaker in activities sponsored by Eli
Lilly) and no other relationships or activities that could
appear to have influenced the submitted work.
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