Jurnal Fix

CNS Drugs (2020) 34:337–365
https://doi.org/10.1007/s40263-020-00711-x
SYSTEMATIC REVIEW
Pharmacological Treatment of Methamphetamine/Amphetamine

Dependence: A Systematic Review
Krista J. Siefried1,2,3 · Liam S. Acheson2 · Nicholas Lintzeris4,5,6 · Nadine Ezard1,2,3,6
Published online: 17 March 2020

© The Author(s) 2020
Abstract
Background Stimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for
68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global con-
cern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research
literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions.
Methods We systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL
and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for
AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evalu-
ated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial
interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions
and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use.
Results Our search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23
individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes)
across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined
populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of
AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexam-
phetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepres-
sants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist
pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic
antidepressants [TCAs]) have not been effective in reducing AMPH/MA use.
Conclusions No pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies
were underpowered and had low treatment completion rates. However, there were positive signals from several agents that
warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should
include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting
conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention.
1 Introduction [1]. Approximately 29 million people worldwide aged

15–65 years were estimated to have consumed ampheta-
Amphetamines and other stimulant drugs are second only mines in the past year to 2017 [1].
to cannabis as the most widely used class of (illicit) drugs Amphetamines refer to both amphetamine (AMPH) and
globally, accounting for 68 million past-year consumers the structurally similar methamphetamines (MA), both of
which are used extra-medically. MA is considered a more
Electronic supplementary material The online version of this potent derivative of AMPH, with a longer duration of action
article (https://doi.org/10.1007/s40263-020-00711-x) contains and increased ability to cross the blood–brain barrier; and
supplementary material, which is available to authorized users. global shifts in the illicit stimulant market have resulted in
the predominance of MA [2, 3].
* Krista J. Siefried
[email protected] Amphetamines act on the central nervous system (CNS)
and acute effects include a heightened sense of alertness;
Extended author information available on the last page of the article
Vol.:(0123456789)
338 K. J. Siefried et al.
amphetamines, methamphetamine or methcathinone” [9].

Key Points In this paper, we have reviewed articles using all of the
above classifications and sometimes interchangeably and our
A comprehensive assessment of the research literature search included both terms. Most reviewed articles had eli-
on pharmacotherapy for amphetamine/methamphetamine gibility criteria that included either the DSM-IV or DSM-V
dependence may inform treatment guidelines and future diagnostic criteria, and so we have combined the terms as
research directions. dependence/use disorder.
We systematically reviewed 43 randomised controlled Globally, it is estimated that 7.4 million people are
trials enrolling 4065 participants and assessing 23 dependent on amphetamines, and that dependence affects
pharmacotherapies for amphetamine/methamphetamine 11% of people who use amphetamines [10]. Regular or
dependence. dependent AMPH/MA use is associated with comorbidities
including depression, anxiety, psychosis and cardiovascular
Outcomes and measures to assess them varied widely, disease, and is due to contextual social factors related to the
making it difficult to synthesise the data; pharmaco- consumption of AMPH/MA, sexually transmitted infections
therapies were most often assessed in defined or biased or blood borne viruses and legal issues [11, 12]. Globally,
populations, and study completion rates were low. the United Nations Office of Drugs and Crime (UNODC)
No pharmacotherapy demonstrated convincing results; estimates around one in seven people with substance use
however, some agents demonstrated promise, suggesting disorders receives treatment [1], and that the proportion of
further, larger studies are required. people with stimulant use disorder in treatment is under-
represented compared with opioid use disorder, for which
Future research should consider the heterogeneity of there are effective treatments combining medication and
amphetamine/methamphetamine dependence and the psychosocial interventions [13].
role of psychosocial intervention. Psychosocial therapies have been trialled for AMPH/MA
dependence with varying efficacy [14, 15]. These include
Cognitive Behavioural Therapy (CBT), Contingency Man-
increased energy; heightened curiosity; anorexia; decreased agement (CM), Motivational Interviewing (MI) and Accept-
fatigue; elevated mood; dose-dependent effects on focus, ance and Commitment Therapy (ACT). Even short periods
attention and concentration; and elevated interest in envi- of intervention with CBT (1–2 sessions) demonstrate a
ronmental stimuli [3, 4]. Extra-medical use of AMPH and reduction in MA use in people who are dependent on MA
MA is usually at higher doses than those prescribed orally, [14]. CM has demonstrated significant reduction in stimu-
and through routes of administration that result in more lant use [16] alone, or in combination with CBT [16] or
rapid onset (inhaled, injected intravenously, intra-nasal, a community reinforcement approach [17]. However, the
per-vaginal, and per-rectal). Extra-medical consumption of effects of psychosocial therapies are often not sustained fol-
amphetamines may be for enjoyment and/or for performance lowing their cessation [14, 18], and are less effective for
enhancement (such as for night-shift workers to enable severe disorder (long duration, frequent use) [19]. There
longer working hours) [5]. have been few controlled evaluations of residential rehabili-
The effects of chronic and regular high-dose AMPH/MA tation approaches for people with AMPH/MA use disorders.
use are more complex than occasional use, and may involve One longitudinal, non-randomised, quasi-controlled study
the development of a substance use disorder—characterised demonstrated that residential rehabilitation was associated
by social and physiological (e.g. tolerance, withdrawal) with decreased MA use 3 months after treatment compared
manifestations [5]. The Diagnostic and Statistical Manual with detoxification or no treatment, but this effect was not
of Mental Disorders Fifth Edition (DSM-V) criteria for maintained to year 3 of follow-up [20].
Stimulant Use Disorder (SUD) and Stimulant Withdrawal One priority for clinicians and researchers alike has been
[6] are listed in Table 1. In the previous version of the DSM to establish an effective pharmacotherapy for SUD. Target
(DSM-IV) [7], the classification listed ‘dependence’ rather pharmacotherapies have considered the mechanism of action
than ‘use disorder’; with ‘moderate to severe’ SUD being of AMPH/MA, which affects neurotransmitters through a
regarded as equivalent to ‘dependence’. The International number of mechanisms. Consumption of MA triggers a cas-
Classification of Diseases (ICD) 10th Revision (ICD-10) cading release of norepinephrine, dopamine and serotonin.
recognises ‘stimulant dependence syndrome’ and ‘stimu- The drug (to a lesser extent) acts as a dopaminergic and
lant withdrawal state’ [8]. However, neither diagnostic tool adrenergic reuptake inhibitor, and in higher concentrations
differentiates between AMPH/MA and other non-cocaine as a monoamine oxidase inhibitor (MAOI) [1, 21]. The CNS
stimulant SUDs; while the 11th Revision of the ICD nar- effects produced by MA are mostly the result of influencing
rows the definition to “stimulant dependence including
Table 1 DSM-V diagnostic criteria for stimulant use disorder
DSM-V: stimulant use disorder [6] DSM-V: stimulant withdrawal [6]
A A pattern of amphetamine-type substance (ATS), cocaine, or other stimulant use leading to clinically A Cessation of (or reduction in) prolonged amphetamine-type substance, cocaine,
significant impairment or distress, as manifested by at least two of the following, occurring within a or other stimulant use
12-month period: B Dysphoric mood and two (or more) of the following physiological changes,
1. The stimulant is often taken in larger amounts or over a longer period than was intended developing within a few hours to several days after Criterion A:
2. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use 1. Fatigue
3. A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or 2. Vivid, unpleasant dreams
recover from its effects 3. Insomnia or hypersomnia
4. Craving, or a strong desire or urge to use the stimulant 4. Increased appetite
5. Recurrent stimulant use resulting in a failure to fulfil major role obligations at work, school, or home 5. Psychomotor retardation or agitation
6. Continued stimulant use despite having persistent or recurrent social or interpersonal problems
C The signs and symptoms of Criterion B cause clinically significant distress or
caused or exacerbated by the effects of the stimulant
impairment in social, occupational, or other important areas of functioning
7. Important social, occupational, or recreational activities are given up or reduced because of stimu-
lant use D The signs or symptoms are not attributable to another medical condition and
8. Recurrent stimulant use in situations where it is physically hazardous are not better explained by another mental disorder, including intoxication or
9. Stimulant use is continued despite knowledge of having a persistent or recurrent physical or psycho- withdrawal from another substance
logical problem that is likely to have been caused or exacerbated by the stimulant
10. Tolerance, as defined by either of the following:
a. A need for markedly increased amounts of the stimulant to achieve intoxication or desired effect
b. A markedly diminished effect with continued use of the same amount of the stimulant
Pharmacological Treatment of Methamphetamine/Amphetamine Dependence
Note: this criterion is not considered to be met for those taking stimulant medications solely under
appropriate medical supervision, such as medications for attention-deficit/hyperactivity disorder or
narcolepsy
11. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for the stimulant (refer to criteria A and B of the criteria
set for Stimulant Withdrawal)
b. The stimulant (or a closely related substance) is taken to relieve or avoid withdrawal symptoms
Note: this criterion is not considered to be met for those taking stimulant medications solely under
appropriate medical supervision, such as medications for attention-deficit/hyperactivity disorder or
narcolepsy
Specify if:
In early remission: After full criteria for SUD were previously met, none of the criteria for SUD have
been met for at least 3 months but for less than 12 months (with the exception that criterion A4,
“Craving, or a strong desire to use the stimulant,” may be met)
In sustained remission: After full criteria for SUD were previously met, none of the criteria for SUD
have been met at any time during a period of 12 months or longer (with the exception of criterion A4,
“Craving, or a strong desire to use the stimulant,” may be met)
Specify if:
In a controlled environment: This additional specifier is used if the individual is in an environment
where access to stimulants is restricted
DSM-V Diagnostic and Statistical Manual of Mental Disorders fifth edition, SUD stimulant use disorder
339
levels of dopamine and norepinephrine, and to a lesser extent LA) independently. Selected publications were read in full
serotonin [1, 21]. by the same two investigators. Divergent selection of publi-
Due to the nature of drug dependence research, studies cations was discussed among the investigators until a con-
often enrol people using multiple types of stimulants or sensus was obtained, and if required a third reviewer (NE)
other drugs. Here we review studies reporting on pharma- resolved disputes. Data were managed in Covidence [23] up
cotherapies for the treatment of SUD or drug dependence to the point of data extraction; due to the large variation in
due to AMPH/MA. Specifically, we reviewed randomised outcome measures, data extraction was completed on iden-
studies of participants with MA or AMPH use disorder or tical spreadsheets by the two reviewers and compared for
dependence (recognising the shift of eligibility criteria and consistency. The selected studies were evaluated for design,
definitions between the DSM-IV and DSM-V) randomised to methodology, inclusion and exclusion criteria, sample size,
a pharmacological intervention and compared with a control pharmacological and (if included) psychosocial interven-
group, with outcomes related to AMPH/MA use and asso- tions, length of follow-up and follow-up schedules, outcome
ciated symptoms (e.g. cravings or withdrawal, as these are variables and measures, results and overall conclusions.
both listed as features of dependence/use disorder). The aim Risk of bias was assessed based on the following fea-
of the present review is to provide clinicians with a summary tures: allocation of participants, blinding of participants or
of the current status of research on pharmacological treat- personnel, study sample, study completion rates, analyses of
ment of AMPH/MA dependence. outcomes (e.g. conservative or not with respect to missing
data, analysis as intention-to-treat), overstated conclusions
and study funding.
2 Methods This review provides a qualitative, narrative report of the
data. Conducting a traditional systematic review and meta-
We approached this report as a systematic review of the analyses is predicated on the assumption of studies reporting
peer-reviewed literature, and present the methods and results on similar outcomes, using similar outcome measures, and
in accordance with the Preferred Reporting Items for Sys- with similar methodology. However, the data we reviewed
tematic Reviews and Meta-Analyses (PRISMA) statement herein was disparate in respect to the reported outcomes and
[22]. measures. This prohibited meta-analysis of the literature but
The eligibility criteria for this review were randomised allowed for a comprehensive report on the current status of
controlled trials (RCTs) enrolling participants (any age or the research.
sex) that assessed a pharmacological treatment (alone or in
combination with psychosocial treatment) for the treatment
of AMPH/MA dependence or use disorder. The search was 3 Results
limited to human trials and with text in the English language.
Included were studies reporting on an outcome related to 3.1 Study Selection and Characteristics
treatment efficacy as defined by AMPH/MA use, associated
symptoms (e.g. cravings or withdrawal) or retention in treat- Our search returned 43 RCTs that met our criteria [24–66].
ment/care. We excluded human studies that were conducted A PRISMA flow diagram is presented in Fig. 1. Forty
in a laboratory environment, studies enrolling primarily (93.0%) of these studies were double-blinded [24–45, 47–55,
non-AMPH/MA-dependent participants, animal studies, 57–65]. In total, 39 (90.7%) were placebo controlled, while
qualitative studies, general reviews and secondary analyses the remaining four studies (9.3%) were designed with a treat-
of RCTs. ment-as-usual or alternate treatment arm as the control [36,
A search of the electronic databases PubMed, EMBASE, 49, 61, 66]. The study settings are described in Table 2. The
CINAHL and SCOPUS was conducted. The basic search studies were published between 1995 and 2019.
strategy for all databases was as follows: (amphetamine OR The 43 studies collectively randomised 4065 participants.
methamphetamine) AND (dependence OR disorder) AND Of the 43 studies, 38 (88%) reported on the total number
(pharmacological treatment OR pharmacotherapy OR drug of participants who completed the study, while five stud-
therapy). Additional studies were obtained by checking the ies (12%) did not [36, 39, 57, 62, 64]. Of the 38 reporting
references of selected articles. There was no start date limi- on study completion rates, the total number of participants
tation on the search—the last search date for inclusion was randomised was 3733 (92% of the total) and of these, 2298
19 June 2019. An example search strategy is included in participants completed the study (61.6%).
Supplementary Fig. 1 (see electronic supplementary mate- Of the 4065 participants reported on in the reviewed stud-
rial [ESM]). ies, 2858 (70.3%) were male. Nine of the 43 studies (21%)
The titles and abstracts of the studies identified by the enrolled only males [24, 29, 30, 34, 46, 52, 55, 57, 58],
search strategy were evaluated by two reviewers (KS and however not all of these were by design. One study [45] did
Pharmacological Treatment of Methamphetamine/Amphetamine Dependence 341
Fig. 1 PRISMA flow diagram
not report the sample by those randomised, only by com- lists the pharmacotherapies reviewed, and the proposed
pleters (in a non-intention-to-treat analysis) and so the total mechanisms of action related to their use in studies of MA/
randomised figure of men versus women was not able to be AMPH dependence.
determined based on randomisation (authors did not respond A summary of the reviewed studies is presented in
to a request for further data). Table 4, and an extended version is available in Supplemen-
Thirty of the 43 studies (69.8%) included participants tary Table 1 (see ESM). In addition, the data collected by
dependent on MA only [24–30, 32–35, 38–41, 44, 45, both reviewers can be located in its entirety in the Supple-
47–50, 53–55, 57, 59–62, 65]; four (9.3%) were on MA/ mentary Data (see ESM).
AMPH [31, 37, 51, 64]; four (9.3%) were on AMPH only
[42, 43, 46, 56]; three (7.0%) were on amphetamine-type 3.2 Risk of Bias Within and Across Studies
stimulants (ATS) and opioids [52, 58, 63] and two (4.7%)
were on MA/cocaine [36, 66]. Risk of bias in individual study methods and reporting are
The 43 studies examined 23 individual pharmacothera- included in Supplementary Table 1 and Supplementary Data
pies, most individually and some in combination. Table 3 (see ESM) as considerations across a number of domains.
Table 2 Study setting and context (9.3%) did not state their funding source [43, 52, 53, 62], and
one study (2.3%) received no funding [34].
Setting Number
of studies
(%) 3.3 Outcomes and Measures
Setting
In total, 55 primary outcome measures were used (inclu-
Outpatient 32 (74.4)
sive of variations) 93 times (as some studies had multiple
Inpatient 5 (11.6)
primary outcomes). The most common primary outcome
Outpatient and inpatient 4 (9.3)
measure reported was abstinence (51 times, 55%), followed
Not reported 2 (4.7)
by cravings (10 times, 11%). For abstinence, urine drug
Location
screens (UDS) were used 41 times (80%) and analysed or
United States of America (USA) 23 (53.5)
defined in 16 different ways. The most common method for
Iran 7 (16.3)
analysing UDS was weekly proportion of AMPH/MA-free
Australia 4 (9.3)
UDS, or overall proportion of AMPH/MA-free UDS. There
Malaysia 2 (4.7)
were 75 distinct secondary outcomes inclusive of variations
Thailand 2 (4.7)
and often analysed differently to the primary outcomes of
Finland 1 (2.3)
the same domain. These were used 158 times. The most
Finland and New Zealand 1 (2.3)
common secondary outcome measure reported was craving
Iceland 1 (2.3)
(25 times), predominantly reported using the visual analogue
Russia 1 (2.3)
scale (VAS) (16 times, 64% of the cravings measures). The
Sweden 1 (2.3)
frequency with which each measure was used is noted in
Enrolling centres
Table 5.
Single site 26 (60.5)
Adherence as an outcome was measured by participant
Multi-site 16 (37.2)
self-report; pill count (i.e. total pills taken divided by total
Not reported/unclear 1 (2.3)
prescribed multiplied by 100 to provide a percentage of
adherence); medication electronic monitoring systems
(MEMS, e.g. an electronic monitor in bottle caps); propor-
Across all studies, allocation of participants was by ran- tion of study staff-administered doses received; or meas-
dom assignment, and all but three studies [46, 56, 66] were ures of metabolites/study drug in plasma. Eleven studies
double-blind. Study completion rates were low, with studies (25.6%) did not report adherence in methods/results. In
reporting the proportion of the sample who did not complete studies reporting both self-report and another measure, there
the protocol as 38.4% of the total randomised. Eighty-three was low concordance between results. For example, in one
percent of studies analysed their results by intention-to- study self-reported adherence was 93% but ad-hoc analy-
treat, while five (12%) [33, 46, 53, 57, 61] were unclear sis of study drug/metabolite in urine results of participants
in this regard and two (5%) [24, 45] did not. Females were randomised to the study drug group were presented in quar-
underrepresented in the data, being only 29.7% of the total tiles, with the top quartile achieving > 85% positive urines
participants. This comprises both studies that only enrolled while the bottom quartile showed ≤ 40% positive urines
males (nine studies, 21%) [24, 29, 30, 34, 46, 52, 55, 57, [25]. Adherence reported by both self-report and MEMS
58] and those enrolling both males and females but with caps demonstrated non-concordance in the two studies
higher male enrolments. Thirty-four (79.1%) of the stud- reporting both—one study reported adherence assessed by
ies we reviewed excluded participants with depression or MEMS caps was 42% as compared with 74% by self-report
psychotic disorders, or those taking an antidepressant or [28], another reported 48.5% versus 74.7% [30]. No study
antipsychotic medication. reporting plasma metabolite/study drug reported a marker
Some authors overstated conclusions; for example, rec- of adherence for placebo. Adherence rates ranged from 21%
ommending treatment uptake despite limited sample sizes, [51] to 100% [55] across studies. Full data for each study are
lack of placebo and/or low completion rates. The studies available in the Supplementary Data (see ESM).
were overwhelmingly government or academic funded
(65.1%, n = 28) [24–28, 30, 32, 33, 35–42, 44, 47, 50, 51, 3.4 Results of Individual Studies
54, 55, 57, 58, 60, 63, 64, 66]. Ten studies (23.3%) were
funded by pharmaceutical companies, or the study drug(s) 3.4.1 Antidepressants
were provided by a pharmaceutical company, or a mix of
funding and drugs were provided by a pharmaceutical com- One study (2%) examined amineptine [300 mg oral (po)
pany [29, 31, 45, 46, 48, 49, 56, 59, 61, 65]. Four studies daily (OD)], an atypical tricyclic antidepressant, in inpatient
Table 3 Pharmacotherapies reviewed

Pharmacotherapy Mechanism of action proposed to be related to use in methamphetamine (MA)/amphetamine n
(AMPH) dependence
Antidepressants
Amineptine Dopamine reuptake inhibition similar to amphetamines, limited noradrenergic effect [85, 86] 1
Mirtazapine Noradrenergic and specific serotonergic antidepressant. Mixed monoamine agonist/antagonist— 3
facilitates release of norepinephrine, serotonin and dopamine in the CNS [87]
Bupropion Atypical, non-tricyclic antidepressant. Selective inhibitor of the neuronal reuptake of norepineph- 6
rine and dopamine, with minimal effect on the reuptake of serotonin and no inhibitory effect on
monoamine oxidase; nicotinic acetylcholine receptor agonist [88]
Sertraline Selective serotonin reuptake inhibitor (SSRI). Blocks the uptake of serotonin [89] 1
Atomoxetine Selective norepinephrine transporter (NET) inhibitor. Potent inhibitor of presynaptic NET, mod- 1
erate inhibitor of serotonin reuptake and weak inhibitor of dopamine uptake, minimal affinity
for other noradrenergic receptors, moderate affinity for 5HT2 and GABAA receptors but poor
affinity for most other receptors [90]
Tricyclic antidepressants (TCAs)

Imipramine TCAs downregulate catecholamine and serotonin receptors, a proliferation of which is induced by 1
chronic cocaine use [91]
Atypical antipsychotics
Aripiprazole Partial agonist activity at dopamine D2 and serotonin 5 HT1A receptors and antagonist activity at 2
serotonin 5HT2A receptors [92]
Aripiprazole + methylphenidate (See above and below) 1
Anticonvulsants
Topiramate Enhances activity of gamma-aminobutyric acid (GABA) at some types of GABAA receptors, 2
glutamate antagonist [93]
Central nervous system stimulants

Dextroamphetamine/dexampheta- Analogue of MA, facilitates the action of dopamine and norepinephrine by blocking reuptake 2
mine from synapse, inhibits action of monoamine oxidase (MAO) [94]
Methylphenidate CNS stimulant, presumed mechanism of action is inhibition of dopamine reuptake without trig- 3
gering the release of dopamine [95]
Other central nervous system agents

Modafinil Exact mechanism of action unknown, thought to bind to dopamine reuptake site with low affinity, 4
increasing extracellular dopamine [96]
GABAB agonist/GABAergic agents

Baclofen + gabapentin Baclofen: Derivative of GABA, inhibits the release of excitatory amino acids (glutamate and 1
aspartate) [97]
Gabapentin: structurally related to GABA neurotransmitter, identification and function of gabap-
entin binding sites remains to be elucidated [98]
GABAergic agents may act on dopamine transmission and reduce the positive reinforcement of
MA [99]
Opioid agonists
Buprenorphine μ-opioid receptor partial agonist, κ-opioid receptor antagonist [100] 1
Buprenorphine + methadone Methadone: opioid agonism and N-methyl-d-aspartate (NMDA) antagonism [101] 1
Opioid antagonists
Naltrexone Opioid receptor antagonist [102]. Animal evidence for involvement of endogenous opioid system 5
in MA-seeking behaviours [103]
5HT3-receptor antagonist
Ondansetron 5HT3-receptor antagonist, potential to attenuate hyper-dopaminergic behaviours [104] 1
Partial cholinergic nicotinic agonist

Varenicline Partial agonist at α4β2 neuronal nicotinic acetylcholine receptors; restoration of MA-related 1
dopaminergic and glutamatergic deficits, cholinergic mechanisms [105]
Table 3 (continued)
Pharmacotherapy Mechanism of action proposed to be related to use in methamphetamine (MA)/amphetamine n
(AMPH) dependence
Glutamatergic agents
N-acetyl cysteine Amino acid. Reduces the release of glutamate from the synapse by stimulation of inhibitory 1
glutamate receptors [106]
N-acetyl cysteine + naltrexone (See above) 1
Riluzole Glutamate regulatory effects in the CNS [107] 1
CRF1 antagonist
Pexacerfont Corticotropin-releasing factor (CRF) binds CRF type 1 receptors during MA withdrawal and a 1
CRF1 antagonist would alleviate the anxiety associated with withdrawal due to CRF [108, 109]
Benzodiazepine antagonist/GABA agonist/H1 histamine receptor
Flumazenil + gabapentin + hydrox- A combination pharmacotherapy regimen with properties including normalising altered dopa- 2
yzine mine, glutamate and GABA neurotransmitter function [110]
Total studies reviewed/total pharmacotherapy agents reviewed 43/23
n Number of reviewed studies investigating this pharmacotherapy
participants for AMPH withdrawal over 14 days [43]. Par- use. None of the six studies achieved a statistically signifi-
ticipants randomised to amineptine were significantly less cant difference in abstinence or reduction in use between
depressed at Day 7 and had improved clinical global impres- the bupropion and placebo arm in planned primary outcome
sion scores at Day 14 in the completer analysis (i.e. only those analyses.
completing study protocol) compared with placebo. However, In one study [60], a post hoc analysis found a statistically
the sample size was small (29 analysed). In terms of feasibil- significant effect for bupropion (150 mg po twice daily [BD])
ity, amineptine has never been approved by the US Federal as compared with placebo when the sample was stratified by
Drug Administration (FDA) and has been suspended in other ‘baseline light-MA consumers’ (0–2 MA-positive UDS in
jurisdictions due to hepatotoxic effects and abuse liability. 2-week baseline period) versus ‘baseline-heavy MA con-
Mirtazapine was examined in three studies (7%). Mir- sumers’ (3–6 MA-positive UDS in 2-week baseline period).
tazapine’s effects on withdrawal symptoms were reported Among ‘baseline light-MA consumers’, the probability of
on twice, yielding conflicting results. In a 2005 study exam- achieving an MA-free week was significantly higher in the
ining mirtazapine (15–60 mg po OD) in AMPH withdrawal bupropion arm as compared with placebo (odds ratio [OR]
[46], Amphetamine Withdrawal Questionnaire (AWQ) [67] of 2.8, p < 0.0001), but there was no statistically significant
scores between baseline and Days 3 and 14 demonstrated difference between bupropion and placebo in ‘baseline-
significant differences favouring mirtazapine over placebo, heavy MA consumers’. A similar planned sub-group analy-
but the study only enrolled 20 participants and the number sis in another study of bupropion (150 mg po BD) for the
analysed was unclear. In contrast, with a primary outcome treatment of MA dependence [33] demonstrated that the sub-
of retention, a 2008 study of mirtazapine (30 mg po OD) for group of participants with ≤ 18 days’ MA use in the 30 days
the treatment of MA withdrawal [31] demonstrated no dif- prior to baseline who were randomised to bupropion had an
ference in retention rates, or the secondary outcome of MA increase in weekly periods of MA abstinence as compared
withdrawal symptoms. The third study [30] aimed to reduce with placebo. In additional subgroup analysis, the male-only
MA use among MA-dependent sexually active men who have participants randomised to bupropion also demonstrated a
sex with men. The proportion of MA-positive UDS was sig- higher proportion of MA-free weeks as compared to placebo
nificantly reduced in both study arms over time but was more [33]. Further analysis determined that two subgroups were
pronounced and quicker in the mirtazapine (30 mg po OD) significantly more likely to have an MA-free week: male
arm compared with the control arm. Participants randomised participants with low baseline use (OR 1.39 and OR 1.34;
to the mirtazapine arm also reduced their high-risk sexual p ≤ 0.001) who were randomised to bupropion; and non-
behaviours (based on a questionnaire), leading the authors depressed female participants with low baseline use (OR
to conclude that mirtazapine decreased both MA use and 1.27; p = 0.02) who were randomised to bupropion.
high-risk sexual behaviours in this population, despite fairly Given bupropion’s licensed indication as a smoking ces-
low adherence rates by MEMS caps and self-report (< 50%). sation aid, unsurprisingly in one study examining the effects
Bupropion was examined in six studies (14%) [26, 33, of bupropion on both smoking and stimulant use, partici-
39, 41, 60, 66]; four reported on AMPH/MA abstinence as pants randomised to bupropion were more likely to reduce
the primary outcome, and two on reduction of AMPH/MA their smoking compared with placebo [66].
Table 4 Reviewed studies
Pharmacotherapy Dose, duration of treatment and Participants Key design elements Results
publication
Antidepressants
Amineptine 300 mg OD over 14 days (Jittiwuti- n = 30, AMPH-dependent, inpa- DB, PB, analysed as ITT, no psy-May improve depressed mood over
kan et al., 1997) [43] tients, drug dependence treatment chotherapy, inpatient, Thailand; first 7 days of treatment (QECCR).
centre, Thailand 300 mg split over 2 uneven doses May improve global state after
14 days
Mirtazapine 30 mg OD over 12 weeks (Colfax n = 60, MA-dependent MSM, outpa- DB, PB, analysed as ITT, CBT and Reduced MA use (UDS), reduced
et al., 2011) [30] tient, USA MI, outpatient, USA sexual risk behaviours, no change to
depressive symptoms (CES-D)
30 mg OD over 14 days (Cruick- n = 31, ATS dependent, recent use, DB, PB, analysed as ITT, narrative Does not improve retention in treat-
shank et al., 2008) [31] outpatient, AUS therapy, outpatient, AUS ment. Does not improve withdrawal,
depression, anxiety, dependence,
use (ACSA, ASI-5, BSI, DASS,
SDS, OTI)
15–30 mg OD over 14 days (Kong- n = 20, AMPH-dependent, correc- NB, PB, analysis unclear, no psy- Reduced withdrawal severity (AWQ).
sakon et al., 2005) [46] tional facility, Thailand chotherapy, correctional facility, May improve anxiety, no change in
Thailand depression (MADRS)
Bupropion 150 mg (SR) BID over 12 weeks n = 204, MA-dependent, DB, PB, analysed as ITT, CBT, No difference in abstinence (UDS).
(Anderson et al., 2015) [26] use < 30 days past month outpatient, USA Contradicts Elkashef 2008
150 mg (SR) BID over 12 weeks n = 156, MA-dependent, treatment DB, PB, analysis not clear, CBT, No difference in abstinence (UDS), in
(Elkashef et al., 2008) [33] seeking outpatient, USA low-use participants (< 18 days per
30) increased abstinence
150 mg (SR) BID over 8 weeks n = 19, MA-dependent, 14–21 years NB, PB, analysed as ITT, group Studies are not feasible in this popula-
(Heinzerling et al., 2013) [39] old counselling, outpatient, USA tion (MA-dependent adolescents)
150 mg (SR) BID over 12 weeks n = 84, MA-dependent, treatment DB, PB, analysed as ITT, CBT, No difference in EOTA (UDS), treat-
(Heinzerling et al., 2014) [41] seeking, used < 29 days of past 30 outpatient, USA ment associated with a higher mean
number of participants with nega-
tive UDS, but very low medication
adherence
150 mg (SR) BID over 12 weeks n = 73, MA-dependent DB, PB, analysed as ITT, CBT and No differences in retention, TES
(Shoptaw et al., 2008) [60] CM, outpatient, USA (UDS), or craving, depression,
smoking (VAS, BDI, cigarette
count)
Bupropion and nicotine inhaler 300 mg (XR) OD over 10 weeks n = 583 MA-dependent, already NB, treatment-as-usual, analysed as No difference in abstinence (UDS and
(Winhusen et al., 2014) [66] engaged as outpatients, smokers ITT, both arms receive SUD coun- self-report), smoking reduced in
selling, treatment arm received treatment arm (CO level, cigarette
smoking cessation and CM, outpa- count), no difference in substance
tients, USA use (UDS)
Sertraline 50 mg BID over 12 weeks (Shoptaw n = 229, MA-dependent 4-arm, sertraline + CM, sertraline Sertraline inferior to PB (UDS), more
et al., 2006) [61] only, PB + CM, PB only, outpa- AEs, sertraline participants more
tient, USA likely to terminate treatment early
345
Table 4 (continued)
346
publication
Atomoxetine 80 mg OD over 16 weeks (Schotten- n = 69, male, ATS and opioid DB, PB, analysed as ITT, manual- Small reduction in ATS use in ato-
feld et al., 2018) [58] dependent, ATS use > 2 days/week based behavioural counselling, all moxetine arm (UDS). Depression
in past month, positive UDS for participants received buprenor- reduced in treatment arm (CES-D).
both substances phine and naloxone as part of Opioid use reduced in PB arm
treatment, inpatient then outpa- (UDS). No change in abstinence
tient, Malaysia (UDS)
Tricyclic antidepressants (TCAs)
Imipramine 150 mg OD over up to 180 days n = 183, MA or cocaine dependent DB, low-dose imipramine control, Higher dose imipramine associated
(Galloway et al., 1994) [36] analysed as ITT, group counsel- with improved treatment retention.
ling, outpatient, USA No difference in MA use, craving,
depression (UDS, VAS, BDI)
Atypical antipsychotics
Aripiprazole 20 mg OD over 12 weeks (Coffin n = 90, MA-dependent, treatment DB, PB, analysed as ITT, CBT and No difference in use (UDS), no dif-
et al., 2013) [28] seeking, positive MA UDS MI, outpatient, USA ference in adherence, sexual risk
behaviours, craving, depression
(MEMS, standard criteria, VAS,
CES-D)
5–10 mg OD over 2 weeks (open n = 37, MA-dependent, MA use DB, PB, analysed as ITT, outpatient, No difference in abstinence (UDS),
label) then 8 weeks (randomised) more than once a week for the Malaysia treatment arm retained longer and
(Sulaiman et al., 2013) [62] past 3 months, has a history of had improved craving (BSCS).
psychosis Reduced psychotic symptoms
(PANSS)
Aripiprazole and methylphenidate 15 mg OD, 54 mg OD over 20 n = 53, AMPH or MA-dependent, 3-arm, aripiprazole vs methylpheni- Aripiprazole inferior, more positive
weeks (Tiihonen et al., 2007) [64] people who inject drugs date vs PB, DB, analysed as ITT, UDS than methylphenidate and
outpatient, Finland PB (UDS). Methylphenidate may
reduce use (UDS). Study stopped
early due to aripiprazole inferiority
and AEs
Anticonvulsants
Topiramate 200 mg OD over 13 weeks (Elkashef n = 140, MA-dependent, positive DB, PB, analysed as ITT, BBCET, No difference in abstinence (UDS),
et al., 2012) [32] UDS outpatient, USA may facilitate reduction in MA use
and severity of dependence (UDS,
CGI-O, CGI-S). No difference
in depression, craving, anxiety
(MADRS, BSCS, ASI)
200 mg OD over 10 weeks (Rezaei n = 62, MA dependent, positive UDS DB, PB, completer analysis, outpa- No difference in use (UDS), reduced
et al., 2016) [55] tients, Iran severity/need (ASI). No difference
in craving or depression (BSCS,
BDRS)
K. J. Siefried et al.
Table 4 (continued)
publication
Central nervous system stimulants

Dexamphetamine 30 mg (SR) BID over 8 weeks (Gal- n = 60 MA-dependent, treatment DB, PB, analysed as ITT, MET, No difference in MA use (UDS),
loway et al., 2011) [35] seeking, positive UDS outpatient, USA significantly improved withdrawal
and craving scores (AWQ, desires
for speed questionnaire, VAS)
110 mg (SR) OD over 16 weeks n = 49, MA-dependent, positive DB, PB, analysed as ITT, CBT, Treatment arm retained in care longer,
(Longo et al., 2010) [50] UDS, use > 3 times per week for outpatient clinic for initial stabi- no differences in use (UDS, hair
past 12 months lisation, then through community analysis, self-report). Reduced with-
pharmacies, AUS drawal symptoms in treatment arm
during stabilisation period (AWQ).
At follow-up, reduced dependence
in treatment arm (LDQ)
Methylphenidate 54 mg OD over 14 weeks (Ling n = 110, MA-dependent DB, PB, analysed as ITT, CBT and No difference in use at any time point;
et al., 2014) [48] CM, outpatient, USA however, change in use larger in
treatment arm (self-report). No
difference in use by UDS. Craving
higher in PB by CCQ-now, no dif-
ference by VAS
54 mg OD over 22 weeks (Miles n = 79, MA- or AMPH-dependent, DB, PB, analysed as ITT, standard No difference in weekly abstinence
et al., 2013) [51] positive UDS care therapy in addition to proto- (UDS). Treatment arm may improve
col, outpatient, New Zealand and retention. No differences in craving,

Finland dependence, medication adherence
(VAS, SDS, pill count)
54 mg OD over 10 weeks (Rezaei n = 56, MA-dependent, positive DB, PB, analysed as ITT, no psy- Reduced craving at endpoint only
et al., 2015) [54] UDS chotherapy, outpatient, Iran (VAS). Use and depressive symp-
toms reduced at end point (UDS,
BDI-II). No difference in depend-
ence, adherence (ASI, pill count)
Other central nervous system agents
Modafinil 200 mg OD and 400 mg OD over 12 n = 210, MA-dependent, positive 3-arm, 200 mg vs 400 mg vs PB. No difference in treatment effective-
weeks (Anderson et al., 2012) [25] UDS DB, analysed as ITT, Matrix CBT, ness by weekly abstinence (UDS).
MET, outpatient, USA No differences in use, dependence,
self-control, ADHD symptoms, HIV
risk, impulsiveness (UDS, ASO,
CGI-O, CGI-S, BSCS, HRBS,
HAM-D, Barratt’s Impulsiveness
Scale)
400 mg OD over 12 weeks (Heinzer- n = 71, MA-dependent, treatment DB, PB, analysed as ITT, CBT and No difference in use (UDS). No dif-
ling et al., 2010) [38] seeking CM, outpatient, USA ference in treatment retention, crav-
ing, depression, cigarette smoking
(VAS, BDI, self-report)
347
Table 4 (continued)
348
publication
200 mg OD over 7 days (Lee et al., n = 20, MA-dependent, last use DB, PB, analysed as ITT, no psy- No difference in retention in care
2013) [47] within 48 h chotherapy, residential units, AUS or withdrawal symptoms (AWQ,
ACSA, ASSA).No difference in
craving, sleep or physiological
measures (VAS, St. Mary’s Hospital
Sleep Questionnaire, heart rate,
blood pressure, respiratory rate)
200 mg OD over 10 weeks (Shearer n = 80, MA-dependent, use 2–3 days DB, PB, analysed as ITT, CBT, No difference in retention or medica-
et al., 2009) [59] per week, positive UDS outpatient, AUS tion adherence (count, MEMS
cap). No difference in use, craving,
dependence (UDS, OTI, self-report,
BSI, VAS, SDS)
GABAB agonist/GABAergic agents
Baclofen and gabapentin 20 mg, 800 mg TID over 16 weeks n = 88, MA-dependent 3-arm, baclofen vs gabapentin vs No difference between arms for MA
(Heinzerling et al., 2006) [40] PB. DB, analysed as ITT, relapse use (UDS). No difference in reten-
prevention group therapy, outpa- tion, depression or craving scores
tient, USA (BDI, VAS)
Opioid agonists
Buprenorphine 6 mg OD over 16 weeks (Salehi n = 40, 18- to 40-year-old men, MA- DB, PB, analysis not clear, Matrix Craving reduced in treatment arm;
et al., 2015) [57] dependent, referred to treatment Model and self-help group, inpa- however, difference disappeared
centre tient, Iran once medication was stopped (CCQ-
Brief). Abstinence improved in
treatment arm, but difference disap-
peared at follow-up (UDS)
Buprenorphine and methadone 8 mg, 40 mg OD over 17 days n = 40, MA-dependent, daily use for DB, two treatment arms, no control, Craving reduced in both arms, sig-
(Ahmadi et al., 2017) [24] past 6 months, abstinent at start analysed as ITT, no psychotherapy, nificantly more in buprenorphine on
of trial inpatient, Iran days 10–14 (out of 17) only (VAS).
All participants completed trial, no
positive UDS recorded. No control
group makes inference difficult
Opioid antagonist
Naltrexone 380 mg (XR) intramuscular injec- n = 100, MA-dependent, men (or DB, PB, analysed as ITT, CBT and No difference in MA use (UDS). No
tion, 4-weekly over 12 weeks identifying male), anal sex with MI, outpatient USA difference in adherence, sexual risk
(Coffin et al., 2018) [29] men while under the influence of behaviours, craving or depression
MA in the past 6 months, positive (Audio Computer-Assisted Self-
UDS Interviewing, VAS, SDS, CES-D,
PHQ2)
50 mg OD over 12 weeks (Jayaram- n = 80, AMPH-dependent, used DB, PB, analysed as ITT, relapse Abstinence higher in treatment arm
Lindström et al., 2008) [42] AMPH on at least 12 days in past prevention therapy, outpatient, (UDS). APMH use (self-report), and
12 weeks Sweden craving (VAS) also reduced in treat-
ment arm. No difference in severity
of dependence (ASI)
Table 4 (continued)
publication
380 mg (XR) over 4 weeks intra- n = 52, MA-dependent, right-handed, DB, PB, completer analysis, no psy- Reduced use in treatment arm (self-
muscular injection, single monthly abstinent from all drugs > 72 h chotherapy, outpatient, USA report), no difference in craving
dose (Kohno et al., 2018) [45] (VAS). Use/craving were both
secondary outcomes
380 mg (XR) intramuscular injec- n = 100, AMPH-dependent, NB, PB, analysed as ITT, MI, CBT No difference in abstinence (UDS).
tion, monthly over 24 weeks use > 10 days in past 31, complete (group and individual), post-detox, No difference in adherence, reten-
(Runarsdottir et al., 2017) [56] 7- to 10-day inpatient detox and outpatient, Iceland tion, other drug use, cravings or
abstinent at start of trial relapse rate (pill count, timeline
follow back, UDS, VAS, ASI)
1000 mg (implant) once (subcuta- n = 100, AMPH and opioid depend- DB, PB, analysed as ITT, no psy- Naltrexone arm retained in care
neous) over 10 weeks (Tiihonen ent > 1-year duration, negative chotherapy, outpatient, Russia longer, reduced overall (AMPH and
et al., 2012) [63] UDS, relative (support person) opioid as aggregate) use (UDS),
willing to participate and stable greater treatment effect (CGI). How-
home address/phone number ever, when just examining AMPH
use, no difference in use (UDS) and
no difference in craving (VAS)
5HT3-receptor antagonist
Ondansetron 0.25 mg, 1 mg, 4 mg BID over 8 n = 150, MA-dependent, treatment 4-arm study, 0.25 mg vs 1 mg vs No differences in abstinence, use,
weeks (Johnson et al., 2008) [44] seeking, positive UDS 4 mg vs PB. DB, analysed as ITT, non-use days or 3-week abstinence
group CBT, outpatient, USA were detected between groups
(UDS). No differences in measures

of dependence, withdrawal, craving,
retention in care (CGI-O, CGI-S,
ASI-Lite, MAWQ, BSCS)
Partial cholinergic nicotinic agonist
Varenicline 1 mg BID over 9 weeks (Briones n = 52, MA-dependent, treatment DB, PB, analysed as ITT, CBT, No difference in EOTA or TES
et al., 2018) [27] seeking, positive UDS inpatient then outpatient, USA (UDS). No difference in time-to-
relapse (UDS); however, treatment
arm reported less cigarette smoking
(cigarette count)
Glutamatergic agents
N-acetyl cysteine (NAC) 1200 mg OD over 8 weeks (Mousavi n = 32, MA-dependent Crossover design, DB, PB, analysis Reduced craving associated with
et al., 2015) [53] not clear, Matrix Model CBT, NAC (CCQ-Brief). Study did not
psychiatric clinic/psychiatric emer- report secondary outcome results
gency department, Iran
N-acetyl cysteine (NAC) and 2400 mg, 200 mg OD over 8 weeks n = 31, AMPH-dependent, MA DB, PB, analysed as ITT, no psy- No difference in craving or use
naltrexone (Grant et al. 2010) [37] primary AMPH used chotherapy, outpatient, USA between arms (Penn Craving Scale,
UDS). No difference in global state,
dependence, depression, anxiety
or quality of life (CGI-S, HAM-
D, HAM-A, SDS, Quality of Life
Index)
349
Table 4 (continued)
350
publication
Riluzole 50 mg BID over 12 weeks (Far- n = 86, MA-dependent DB, PB, analysed as ITT, Matrix Treatment arm reported higher EOTA
ahzadi et al., 2019) [34] Model CBT, outpatient, Iran (UDS). Treatment associated with
improvement in dependence scores,
withdrawal, craving, depression
(ASSA, AWQ, Stimulant Craving
Questionnaire, VAS, HAM-D)
CRF1 antagonist
Pexacerfont 300 mg OD over 3 weeks (Morabbi n = 51, men, AMPH or opioid Tapering dose over 3 weeks, DB, Craving was reduced in the treat-
et al., 2018) [52] dependent PB, analysed as ITT, no psycho- ment group (VAS), no difference
therapy, residential camps, Iran in EOTA (UDS). Temptation and
depression scales were improved in
treatment arm (Beck Depression,
VAS), no differences in treatment
effectiveness, withdrawal or anxiety
(UDS, AWQ, Beck Anxiety). Did
not present findings for AMPH only,
all in aggregate with opioids
Benzodiazepine antagonist/GABA agonist/H1 histamine receptor
Flumazenil, gabapentin and 2 mg, 1200 mg, 50 mg per protocol n = 120, MA-dependent, treatment DB, PB, analysed as ITT, CBT, No difference in rates of abstinence
hydroxyzine over 40 days (Ling et al., 2012) seeking, MA use > 4 days in the inpatients and outpatients, USA (UDS). No difference in craving,
[49] past 30 use, retention (BSCS, ASI, UDS)
2 mg, 1200 mg, 50 mg per protocol n = 135, MA-dependent, treatment DB, PB, analysed as ITT, Matrix Treatment arm reported reduced crav-
over 30 days (Urschel et al., 2011) seeking, last use within 3 days Model CBT, CM, outpatients, ing scores (VAS). No difference in
[65] USA use by UDS (imputing missed doses
as positive), reduced use in treat-
ment arm by self-report; conflicts
with Ling, 2011; however, this study
included CM and Ling, 2011 did not
ACSA Amphetamine Cessation Symptoms Assessment, ADHD attention-deficit hyperactivity disorder, AE adverse event, AMPH amphetamine, ASI Addiction Severity Index, ASI-Lite Addic-
tion Severity Index-Lite, ASI-5 Addiction Severity Index-5th edition, ASSA Amphetamine Selective Severity Assessment, ATS amphetamine-type substance, AUS Australia, AWQ Amphetamine
Withdrawal Questionnaire, BBCET Brief Behavioural Compliance Enhancement Therapy, BDI Beck Depression Inventory, BDI-II Beck Depression Index-Version 2, BDRS Bipolar Depression
Rating Scale, BID twice daily, BSCS Brief Self-Control Scale, BSI Brief Symptom Inventory, CBT cognitive behavioural therapy, CCQ-BRIEF Cocaine Craving Questionnaire-Brief, CCQ-Now
Cocaine Craving Questionnaire-Now, CES-D Centre for Epidemiological Studies depression scale, CGI-O Clinical Global Impression-Observer, CGI-S Clinical Global Impression-Self, CM
contingency management, CO carbon monoxide, DASS Depression Anxiety Stress Score, DB double-blind, EOTA end-of-treatment abstinence, HAM-A Hamilton Anxiety Scale, HAM-D Ham-
ilton Depression Scale, HIV human immunodeficiency virus, HRBS Health-Related Behaviours Survey, ITT Intention-to-treat, LDQ Leeds Depression Questionnaire, MA methamphetamine,
MADRS Montgomery–Åsberg Depression Rating Scale, MAWQ Methamphetamine Withdrawal Questionnaire, MEMS Medication Event Monitoring System, MET motivational enhancement
therapy, MI motivational interviewing, MSM men who have sex with men, NAC N-acetyl cysteine, NB not blinded, OD once daily, OTI Opioid Treatment Index, PANSS Positive and Negative
Syndrome Scale, PB placebo-controlled, PHQ2 Patient Health Questionnaire-2, QECCR Questionnaire for Evaluating Cocaine Craving and related Responses, SDS Severity of Dependence
Scale, SR sustained-release, SUD substance use disorder, TES Treatment Effectiveness Score, TID three times daily, UDS urine drug screen, VAS Visual Analogue Scale, XR extended release
Table 5 Outcomes and measures
Outcome assessed Measures used Variations on analysis
Primary outcomes
Abstinence (from AMPH, MA, Urine drug screen (UDS) (n = 41) Variations in cut-off points and measures:
or amphetamine-type substance • 1000 ng/mL (n = 1)
[ATS]) (n = 51) • 300 ng/mL (n = 2)
• Confirmed by mass spectrometry
– 78 ng/ml (n = 1)
– < 300 ng/mL (n = 1)
Comparing proportion of participants in each group demonstrating abstinence in the final 2 weeks of study—absti-
nence defined by having all UDS test negative and providing at least two UDS per week (n = 1)
Comparing proportion of participants in each group demonstrating abstinence in the final 2 weeks of study—absti-
nence defined by having all UDS test negative and providing all UDS in final 2 weeks of study (n = 3)
Negative UDS during final 2 weeks of treatment and no more than 1 of 3 possible UDS missing per week (n = 2)
Weekly proportion of negative UDS (or weekly proportion of positive UDS) (n = 5)
Proportion of UDS testing negative during the study (n = 5)
Treatment Effectiveness Score (TES):
• the sum of the number of negative (AMPH, MA, ATS) UDS during the treatment phase per participant (n = 3)
• average of the sum of negative UDS submitted per participant in each treatment arm (n = 1)
Joint Probability Index: number of negative (AMPH, MA, ATS) UDS submitted by each participant in each treat-
ment group at time point (end-of-treatment or follow-up visit) divided by the number of participants randomised
to that treatment group (n = 3)

Longest period of uninterrupted abstinence (n = 3)
Percentage of participants with at least
• 2 weeks’ abstinence (n = 2)
• 3 weeks’ abstinence (n = 3)
Drug ‘free’ week: A week in which all non-missing urine samples in the week (3 samples/week) were drug free
(AMPH, MA, ATS) (n = 1)
Negative ‘use week’ (n = 1) UDS collected 3 times per week: ‘use week’ defined as each 7-day period beginning with first dose of study drug
• A ‘positive use week’ was any week in which ≥ 1 UDS was MA-positive
• A ‘negative use week’ was any week in which all UDS were MA-negative, even if only 1–2 UDS were collected
• Data were considered missing if 0 UDS were collected
Self-report (n = 4) Abstinence for 21 days any time during the study period (n = 2)
Days per week (e.g. self-reported non-use days) (n = 1)
Frequency of use in prior 2 weeks (AMPH, MA, ATS) (n = 1)
Drug diaries • 28 days prospective (n = 1)
Timeline Follow Back (TLFB) (n = 2)
Opiate Treatment Index (OTI) (n = 1) • For self-reported MA use substituted for opiates
Hair analysis (n = 1)
351
Table 5 (continued)
352
Changed use/reduction in use Reduction in UDS-positive metabo- Decrease in average weekly log10 median urine MA concentrations over treatment period
(n = 7) lites (n = 3)
Overall change in proportion of posi- • Over study period (n = 2)
tive UDS • Per week (n = 1)
(AMPH, MA, ATS) (n = 3)
New MA use (n = 1) Determined by MA-positive first sample; following sample with no MA; MA detected in subsequent sample;
following sample with MA detected; MA detected in subsequent sample in greater quantities than would be
expected on the basis of mean half-life plus 2 standard deviations (SD); participant self-reports new use of MA
since prior sample
Treatment efficacy (n = 3) UDS (n = 3) • Number of non-use weeks (n = 1)
• Number of negative UDS during treatment (n = 1)
• Number of abstinence events (n = 1)
Amphetamine Withdrawal Questionnaire (AWQ) (n = 1)
Craving (n = 10) Visual analogue scales (VAS) (n = 5) • 10 mm (point) VAS (n = 1)
• 100 mm (point) VAS (n = 1)
Brief Substance Craving Scale (BSCS) (n = 1)
Questionnaire for Evaluating Cocaine Craving and Related Responses (QECCRR) (n = 1)
Cocaine Craving Questionnaire—Brief (CCQ-B) (n = 2)
Penn Craving Scale (n = 1)
Withdrawal (n = 3) AWQ (n = 1)
Amphetamine Cessation Symptoms Assessment (ACSA) (n = 1)
Amphetamine Selective Severity Assessment (ASSA) (n = 1)
Dependence (n = 3) Leeds Dependence Questionnaire (LDQ) (n = 1)
Addiction Severity Index (ASI)/ASI-Lite (n = 1)
Severity of Dependence Scale (SDS) (n = 1)
Depression (n = 1) Beck Depression Inventory (BDI) (n = 1)
Psychopathology (n = 1) Brief Symptom Inventory (BSI) (n = 1)
Clinical Impression (n = 1) Clinical Global Impression Scale (CGI) (n = 1)
Retention in treatment/study • Average duration of time in care (n = 3)
(n = 5) • Number of participants who complete treatment (n = 2)
Participant satisfaction (n = 3) • Type and number of adverse events (AEs) (n = 3)
Feasibility (n = 2) • Feasibility to recruit (n = 1)
• Tolerability of study drug (n = 1)
Adherence (n = 3) Pharmacy records (n = 1)
Medication Event Monitoring System (MEMS) caps (n = 1)
Study drug metabolites in urine (n = 1)
Table 5 (continued)
Secondary outcomes
Abstinence (from AMPH, MA, or UDS (n = 10) Comparing proportion of participants in each group demonstrating abstinence in the final 2 weeks of study—absti-
ATS) (n = 22) nence defined by having all UDS test negative and providing at least two UDS per week (n = 2)
Weekly proportion of negative UDS (or weekly proportion of positive UDS) (n = 2)
Proportion of UDS testing negative during the study (n = 2)
Treatment Effectiveness Score (TES):
• average of the sum of negative UDS submitted per participant in each treatment arm (n = 1)
Self-report Abstinence for 21 days any time during the study period (n = 1)
Days since last use (n = 1)
Days per week (e.g. self-reported use or non-use days) (n = 4)
Frequency of use in prior 2 weeks (AMPH, MA, ATS) (n = 1)
Drug-free days (n = 1)
TLFB (n = 3)
OTI (n = 1) • Drug use subscale
Changed use/ Decrease in average weekly log10 median urine MA concentrations over treatment period (n = 2)
reduction in use (n = 4) Time to relapse (n = 2) • Amongst those who previously achieved abstinence (n = 1)
• Relapse for participants with negative MA UDS at baseline (n = 1)
Craving (n = 25) VAS (n = 16) • 7 mm (point) VAS (n = 1)
• 100 mm (point) VAS (n = 5)

BSCS (n = 6)
Stimulant Craving Questionnaire (STCQ) (n = 1)
‘Desires for Speed’ modification of ‘Desires for Alcohol’ Questionnaire (n = 1)
Craving Questionnaire—Now version (CQ-Now) (n = 1)
Withdrawal (n = 5) AWQ (n = 3)
ACSA (n = 1)
Methamphetamine Withdrawal Questionnaire (MAWQ) (n = 1)
Dependence (n = 14) ASI/ASI-Lite (n = 10)
SDS (n = 3)
ASSA (n = 1)
Depression (n = 20) BDI (n = 8)
Montgomery-Åsberg Depression Rating Scale (n = 2)
Centre for Epidemiologic Studies Depression Scale (CES-D) (n = 4)
Hamilton Depression Rating Scale (HAM-D) (n = 4)
Depression Anxiety Stress Scale • Full scale and sub-scores
(DASS) (n = 1)
Beck Depression Inventory II (BDI-II) (n = 1)
353
Table 5 (continued)
354
Anxiety (n = 3) Hamilton Rating Scale for Anxiety (HAM-A) (n = 1)

Beck Anxiety Inventory (n = 1)
Anxiety State Index (n = 1)
Psychological distress (n = 1) Patient Health Questionnaire-2 (PHQ-2) (n = 1)
Psychopathology (n = 2) BSI (n = 1)
Positive and Negative Symptoms Scale (PANSS) (n = 1)
Clinical impression (n = 9) Clinical Global Impression Scales: Observer (CGI-O) (n = 3)
Clinical Global Impression Scales: Self (CGI-S) (n = 4)
Retention in treatment/study • Days admitted as inpatient (n = 3)
(n = 11) • Number of days received study drugs following first dose (n = 1)
• Number of days attended from randomisation to the final study visit (n = 1)
• Provision of at least one UDS during Week 8 of study (n = 1)
• Days between first study drug infusion and last clinic visit (n = 1)
• Study drug doses collected (n = 1)
• Number of treatment days during outpatient treatment until the last clinical contact (n = 3)
Participant satisfaction (n = 1) • Percentage of participants completing active medication, mean number weeks in treatment (n = 1)
Adherence (n = 13) Self-report using AIDS Clinical Trials Group Questionnaire (ACTG) (n = 1)
Pill count (n = 7)
MEMS caps (n = 2)
Study drug metabolites in urine (n = 2)
Dose logs (n = 1)
Risk behaviour (n = 4) HIV Risk-Taking Behaviour Scale (HRBS) (n = 1)
HIV Risk Assessment Battery (n = 1)
Audio Computer-Assisted Interview • Number male partners
(ACASI) for self-report (n = 2) • Number male partners with whom MA used
• Episodes anal sex (insertive/receptive) with HIV serodiscordant partners
• Drug use
• Substance use treatment
• Sexual risk behaviour
Attention-deficit hyperactivity Adult ADHD Clinical Diagnostic Scale (ACDS) (n = 1)
disorder (ADHD) (n = 3) Adult ADHD Investigator Symptom Rating Scale (AISRS) (n = 1)
Barratt Impulsiveness Scale (n = 1)
Neuro-cognition (n = 1) Cambridge Neuropsychological Test Automated Battery (CANTAB) (n = 1)
Safety (n = 7) Serious adverse events (SAEs)/adverse events (AEs) (n = 3)
Physiological indicators (n = 4) • Vital statistics (n = 3)
• Electrocardiogram (ECG) results (n = 1)
One study (2%) examined sertraline (50 mg po BD),

along with CM for the treatment of MA dependence over
14 weeks [61]. The four study arms were sertraline only,
sertraline and CM, placebo only, placebo and CM. There
was no statistically significant main or interaction effect of
either sertraline or CM for measures of MA use. In fact,
those in the sertraline-only arm were significantly less likely
to achieve 3-week abstinence and significantly more likely to
have an MA-positive UDS throughout the study compared
with other study arms.
One study examined imipramine (150 mg po OD) for the
treatment of cocaine and MA dependence [36]. The primary
outcome was retention in care, and the survival analysis indi-
cated that higher doses of imipramine were associated with
enhanced retention in treatment which in turn was associated
with more frequent clinical contacts. There were no statis-
• Weekly number cigarettes in smoker subgroup (n = 2)
tically significant differences between arms on secondary

outcomes of time since last MA use, cravings or depres-
sion. Notably, 32 of the 183 participants (17.4%) were MA
dependent, the rest were cocaine dependent. This study was
not placebo controlled, control participants were provided
with a reduced dose of imipramine (10 mg versus 150 mg
daily), primarily to increase blinding efficacy and accept-
• Carbon monoxide tests (n = 1)
ability by staff and participants.

A study of atomoxetine (80 mg po OD), a selective nor-
epinephrine (noradrenaline) reuptake inhibitor (SNRI),
Variations on analysis
randomised 69 opioid and ATS-dependent participants to

16 weeks of treatment, assessing ATS use as the primary
Abnormal Involuntary Movement Scale (AIMS) (n = 1)
Global Assessment of Functioning (GAF) score (n = 1)
outcome [58]. The proportion of ATS-negative UDS was

higher in the atomoxetine arm compared with placebo, but
St Mary’s Hospital Sleep Questionnaire (n = 1)
achieved only a small effect size, while there was no statisti-

AMPH amphetamine, HIV human immunodeficiency virus, MA methamphetamine
The Quality of Life Inventory (QoLI) (n = 1)
cally significant difference in days abstinent. For secondary

outcomes, the proportion of morphine-negative UDS was
Athens Insomnia Scale (AIS-5) (n = 1)
Barnes Akathisia Scale (BAS) (n = 1)

Simpson Angus Scale (SAS) (n = 1)
lower for the atomoxetine arm, while the depression scores

Liver function tests (LFTs) (n = 1)
Sheehan Disability Scale (n = 1)
were significantly reduced in the atomoxetine arm compared

with placebo [58].
3.4.2 Atypical Antipsychotics
Euro-QoL (n = 1)
Cigarettes (n = 3)
Measures used
Aripiprazole was assessed in two studies on its own [28,

62], and once in a study that also had a second active agent
arm—methylphenidate [64]. Aripiprazole (20 mg po OD)
for the treatment of MA dependence was no more effective
than placebo in reducing MA consumption or reduction in
MA-positive UDS [28]. In another study of the treatment of
Other adverse effects (n = 4)
MA dependence and associated psychoses, participants ran-

Other substance use (n = 3)
domised to aripiprazole (5–10 mg po OD) demonstrated no

Quality of life (n = 3)
significant difference in abstinence compared with placebo

Table 5 (continued)
Disability (n = 1)
Outcome assessed
[62]. However, those randomised to the aripiprazole arm

were more likely to be retained in treatment, and to demon-
Sleep (n = 2)
strate a decrease on symptom scores for psychopathology on

the Positive and Negative Symptoms Scale (PANSS) [62].
A study investigating aripiprazole versus methylpheni- severity compared with placebo [50]; however, participants
date for AMPH dependence (primary outcome AMPH use, were outpatients and continued MA use complicates the
secondary outcomes change in use and retention) enrolled interpretation of withdrawal scores.
three study arms: aripiprazole 15 mg daily, methylphenidate Another study examined sustained-release oral dexam-
54 mg daily or placebo [64]. The aripiprazole study arm phetamine (30 mg po BD) for 60 MA-dependent participants
had significantly more AMPH-positive UDS compared with [35]. The primary outcomes included safety and efficacy
either the methylphenidate or placebo arms. The study was defined as abstinence from MA—measured by a new MA-
ceased early due to this finding at interim analysis. The anal- positive UDS (measured twice weekly) and self-reported
ysis also demonstrated that participants randomised to the MA consumption. There was no significant difference
methylphenidate arm returned significantly fewer AMPH- between study groups on measures of MA consumption;
positive UDS than placebo. In addition, two participants (4% however, the participants randomised to dexamphetamine
of randomised participants) in the aripiprazole arm discon- reported significantly reduced MA withdrawal severity and
tinued the study due to adverse events. cravings compared with placebo [35], although these were
secondary outcome measures and again in the context of
3.4.3 Anticonvulsants continued MA use by outpatient participants.
Three studies examined sustained/extended-release oral
Topiramate was investigated in two studies reviewed here. methylphenidate in addition to the study reporting methylphe-
One study examined topiramate (200 mg po OD) in MA- nidate versus aripiprazole discussed earlier. All three were in
dependent adults (n = 140 randomised, 77 completed study) the outpatient setting and used the same dose (54 mg po OD).
with the primary outcome being MA abstinence at Week 12 The first randomised 79 MA/AMPH-dependent par-
[32]. While there was no statistically significant difference ticipants for 22 weeks to methylphenidate or placebo, with
between topiramate and placebo on the primary outcome, a abstinence (measured by twice-weekly UDS, and defined
higher proportion of participants randomised to topiramate as the weekly percentage of AMPH/MA-positive results) as
reduced their MA use compared with placebo. the primary outcome [51]. Twenty-seven participants (34%)
In a separate study, topiramate (200 mg po OD) for MA completed the study. In intention-to-treat analysis there were
dependence was examined in 62 males and analysed in 57, no differences in abstinence or study retention rates (defined
who were all on prescribed methadone for opiate replacement by number of doses collected), although the methylphenidate
therapy [55], with the outcomes of interest being depend- arm achieved higher study retention from Week 6. The sam-
ence severity, cravings, depression and MA use. There was ple was heterogeneous, as participants were enrolled in both
a statistically significant difference between groups on the Finland, where all participants took intravenous AMPH, and
Addiction Severity Index (drug use severity and drug need New Zealand, where all participants smoked MA, but the
domains) that favoured the topiramate arm; however, there results were analysed in aggregate. There was no concomi-
was no statistically significant difference in cravings or tant psychosocial therapy.
depression symptoms between the study groups. Participants Another study enrolled 110 MA-dependent participants
randomised to topiramate returned significantly fewer MA- in the USA with active study drug for 10 weeks followed by
positive UDS at Week 6, but this result was not sustained 4 weeks of blinded placebo treatment to encourage follow-up
throughout the final 4 weeks of the treatment period [55]. [48]. Participants received weekly CBT and CM. There was
no difference between study groups in self-reported MA use
3.4.4 Central Nervous System Stimulants in planned analysis of the final 30 days of treatment; how-
ever, a secondary analysis of data from baseline to Week 10
Two studies reviewed examined dexamphetamine as stimu- found there were significantly fewer self-reported MA use
lant agonist treatment. The first study reviewed 49 partici- episodes in the methylphenidate arm than placebo.
pants with MA dependence and prescribed 110 mg daily The final study enrolled 56 Iranian MA-dependent par-
sustained-release oral dexamphetamine over 16 weeks. It ticipants for 10 weeks of treatment examining craving as the
measured MA use by self-report and analysis of hair, sever- primary outcome [54]. At Week 10 of the study there was a
ity of dependence over time and treatment retention—find- reduction in craving in the treatment arm, and the treatment
ing no statistically significant difference between the study arm demonstrated fewer positive UDS and reduced depres-
groups on planned analysis. Post-hoc analysis demonstrated sive symptoms at Week 10 compared with the placebo arm.
a reduction in MA dependence symptoms in the dexamphet-
amine arm compared with placebo using the Leeds Depend- 3.4.5 Other Central Nervous System Agents
ence Questionnaire [50]. Secondary analysis included
withdrawal symptoms. The participants randomised to dexa- Modafinil was examined in four studies reviewed here,
mphetamine demonstrated a greater reduction in withdrawal in doses of 200–400 mg daily. Three were conducted in
outpatient settings [25, 38, 59] and one in an inpatient with- study reported on naltrexone and n-acetyl cysteine (see
drawal setting [47]. One pilot withdrawal study examined below).
feasibility and withdrawal symptoms in 19 participants pre- Results of the studies are conflicting. There was no dif-
scribed 7 days of modafinil (200 mg po OD Days 1–5 and ference in MA use by UDS in the treatment arm compared
100 mg po OD Days 6–7) versus placebo. There were no with placebo in the extended-release studies [29, 56]. One
differences between study arms in retention or withdrawal study of naltrexone (a single 4-week injection) reported on
symptoms [47]. None of the other three studies demonstrated 37 of 52 randomised participants and found a reduction
a difference in MA use, adherence or retention between in past 30-day MA use, but relied entirely on self-report
study arms. One study analysed a subset of participants with [45], and there was a crossover in primary outcome meas-
the greatest adherence (> 85%) to study treatment compared ures given the past 30-day questionnaires were adminis-
with other study participants randomised to modafinil and tered within 3 weeks of each other. One outpatient study
observed greater abstinence from MA in the > 85% adherent of AMPH-dependent participants in Sweden reported fewer
participants; however, the comparison did not include the AMPH-positive UDS in the naltrexone (50 mg po OD) arm
placebo group and external confounders were not identified compared with placebo [42], a result shared by the study
or controlled for [25]. examining naltrexone implants (1000 mg subcutaneously)
administered to Russian participants with AMPH depend-
3.4.6 GABA Agonist/GABAergic Agents ence [63].
One 16-week outpatient study of 88 MA-dependent par- 3.4.9 5HT3‑Receptor Antagonist

ticipants examined baclofen (20 mg OD three times daily
[TDS]) and gabapentin (800 mg OD TDS) for their effects A single study has investigated ondansetron for the treat-
on MA use [40]. Secondary outcomes included treatment ment of MA dependence [44]. This four-arm trial assessed
retention, depression, cravings and adverse events. No differ- different doses of ondansetron (0.5 mg, 2 mg, 8 mg po OD)
ences were observed between study arms. Post-hoc analysis against placebo in measures of abstinence, use, severity of
demonstrated higher probability of MA-negative urines was dependence, withdrawal, craving and retention in treatment.
associated with medication adherence in all arms, higher in There was no observable difference in any outcome measure
the treatment arm. between doses or against placebo. The authors suggest that
the nil result may be due to the short half-life of ondansetron
3.4.7 Opioid Agonists (approximately 5 h) and suggest a sustained-release formula-
tion or more aggressive dosing may give more efficacious
Two Iranian studies reviewed examined opioid agonists, results. At the time of this review no follow-up studies had
one buprenorphine [57] and one buprenorphine and metha- been conducted.
done [24]. Both studies were in MA-dependent inpatient
males with no co-occurring substance use disorder. In one 3.4.10 Partial Cholinergic Nicotinic Agonists
16-week study of 40 participants with concomitant psycho-
social therapy (Matrix model), reduction in MA cravings A single, recent American study assessed varenicline (1 mg
and fewer MA-positive UDS were demonstrated among the po BD) as a pharmacotherapy for MA dependence [27].
buprenorphine (6 mg sublingual [SL, i.e. applied under the There were no differences between treatment and placebo
tongue] OD) arm as compared with the placebo arm dur- arms for any measures of dependence; however, there was
ing the treatment phase, trending back to baseline following a reduction in cigarettes smoked in the treatment arm (con-
cessation of medication [57]. The second study examined sistent with its licensed indication as a smoking cessation
buprenorphine (8 mg SL OD) versus methadone (40 mg po medication).
OD) over 17 days, with 20 participants in each study arm.
There was a reduction in MA craving compared with pla- 3.4.11 Glutamatergic Agents
cebo, and no participants produced MA-positive UDS in
the study period, but the setting was a controlled inpatient Glutamatergic agents have been assessed, as either rilu-
environment [24]. zole [34], N-acetyl cysteine (NAC) [53], or a combination
of NAC and naltrexone [37]. A recent trial of Iranian men
3.4.8 Opioid Antagonists found that riluzole (50 mg po OD) was associated with
higher rates of retention in treatment and abstinence at Week
Five studies examined the opioid antagonist naltrexone, 12, as well as overall improvements in a range of second-
including two that used an extended-release formulation ary outcomes [34]. Efficacy for NAC is conflicted, however.
[29, 56] and one that used an implant [63]. An additional When trialled as a combination of NAC (escalating dose to
2400 mg po OD) with naltrexone (escalating dose to 200 mg makes it impossible to recommend any pharmacotherapy
po OD), there was no difference between arms in measures as effective at this point in time, although there are some
of craving, use or psychological scales [37]. Mousavi et al., promising signals.
however, found that NAC treatment (escalating dose to
1200 mg po OD) was associated with a reduction in crav- 4.2 Reduction in Use
ing. This paper did not report on secondary outcomes [53].
Both studies had low participant numbers (n = 31 and n = 32, There are a few pharmacotherapy candidates for the treat-
respectively). Mousavi et al. [53] allowed weekly ‘matrix ment of AMPH/MA dependence/use disorder that dem-
model’ psychological therapy to all participants, while Grant onstrate some weak positive signals. The most consistent
et al. [37] did not provide any psychosocial support, and this positive findings have been demonstrated with stimulant
may explain the discrepancies in results. agonist treatment (dexamphetamine and methylphenidate),
naltrexone and topiramate. Less consistent benefits have
3.4.12 CRF1 Antagonist been shown with bupropion, the glutamatergic agent, rilu-
zole, and antidepressant mirtazapine, whilst in general, anti-
We reviewed pexacerfont in one study, a 3-week trial of depressant medications (e.g. SSRIs, TCAs) have not been
51 Iranian men within residential treatment camps where effective in reducing AMPH/MA use.
treatment is not normally provided [52]. Dosing was tapered Substitution/replacement medication approaches (i.e.
from 300 mg po OD for the first week, to 200 mg po OD agonist therapies) have demonstrated positive outcomes for
in Week 2 and 100 mg po OD in Week 3. While measures other drug classes (e.g. nicotine replacement for tobacco/
of craving reduced significantly more in the treatment arm cigarettes, methadone for opioids, nabiximols for cannabis).
than placebo, there was no difference in end-of-treatment Stimulant agonist treatment with dexamphetamine demon-
abstinence between groups. Additionally, levels of tempta- strated promising results in post hoc and secondary analyses
tion and depression, but not anxiety, withdrawal severity, in the two studies reviewed here [35, 50], but predominantly
or treatment effectiveness, improved favouring treatment. with regard to withdrawal and craving symptoms in the con-
text of continued AMPH/MA use. Methylphenidate deliv-
3.4.13 Benzodiazepine Antagonist/GABA Agonist/H1 ered mixed results when assessed for varying outcomes. One
Histamine Receptor study demonstrating higher retention rates in methylpheni-
date arms compared with placebo was limited by a heteroge-
The combination therapy of flumazenil (2 mg intravenous neous study sample [51]. Conversely, lower MA use by self-
Days 1, 2, 3, 21, 22), gabapentin (titrated up to 1200 mg po report in the methylphenidate arm compared with placebo
OD) and hydroxyzine (50 mg po pre-intravenous medication was reported in a study (n = 110) that concurrently used CBT
and as required for sleep), marketed and trademarked as the and CM [48]; and reductions in craving and MA-positive
‘PROMETA protocol’, has been assessed twice in RCTs for UDS was reported in a study enrolling 56 participants [54].
MA dependence. Both trials were similar in terms of partici- Other work in this area is ongoing. One study [68] is cur-
pant numbers and followed an identical medication protocol; rently examining 12 weeks of lisdexamfetamine (a pro-drug
however, results were conflicting. A 30-day trial found sig- of dexamphetamine) versus placebo in a double-blind, RCT
nificantly improved craving scores, but no difference in use of MA-dependent (for at least 2 years) adults with baseline
(missing UDS imputed as positive) [65]. However, a 40-day use of at least 14 of the prior 28 days.
trial conducted the same year found no differences in any The studies we reviewed here that examined the opioid
measures, including craving [49]. antagonist naltrexone demonstrated conflicting results, but
there were signals in both daily oral [42] and long-acting
formulations (i.e. subcutaneous implant) [63] that naltrex-
4 Discussion one may reduce AMPH use. Recently, a large (n = 403) USA
study of extended-release naltrexone (380 mg by intramuscu-
4.1 Summary of Evidence lar injection every 3 weeks) and bupropion (450 mg po OD)
versus placebo completed enrolment. The primary outcome
We reviewed 43 RCTs reporting on 4065 participants that in this study was the percentage of UDS negative for MA
examined 23 pharmacotherapies for SUD or drug depend- during the 12 weeks of treatment, and results are pending
ence due to AMPH/MA with various outcomes pertaining (Trivedi et al.; ClinicalTrials.gov identifier: NCT03078075).
to use and associated symptoms. While some drugs demon- Topiramate was assessed in two studies reviewed here
strated results that were statistically significantly better than [32, 55], demonstrating reduced use and addiction severity
placebo outcomes, the studies were generally small and the compared with placebo. Furthermore, a secondary analysis
samples biased and study protocol completion was low. This of Elkashef et al. [32] found higher responders within groups
in a latent class analysis [69], suggesting further studies with AMPH/MA withdrawal. However, five studies in our review
different eligibility criteria are warranted. focused on pharmacotherapy for MA withdrawal with with-
In baseline light-MA users or in men, bupropion demon- drawal measures as the primary outcome. Three of these
strated a reduction in MA use [60]. Encouragingly, it also were included in a 2009 Cochrane Review [73] of pharma-
reduced concurrent tobacco use in participants [66]. There cotherapies for AMPH withdrawal: a 1997 Thai study of
are known interaction effects of nicotine and methampheta- amineptine in AMPH withdrawal [43], a 2005 study exam-
mine and a potential role of nicotine use in maintaining their ining mirtazapine in AMPH withdrawal [46] and a 2008
co-use [70]. study of mirtazapine in MA withdrawal [31]. The Cochrane
One study of 86 men examining the benzothiazole rilu- Review included a fourth study not reviewed here. The
zole demonstrated positive results [34], with participants results of the meta-analyses undertaken in the Cochrane
randomised to riluzole more likely to be retained in treat- review demonstrated that amineptine did not reduce with-
ment and provide MA-negative UDS than those randomised drawal symptoms or cravings compared with placebo, while
to placebo. However, the study excluded participants who the mirtazapine studies yielded mixed results, with one study
smoked cigarettes > 3 days per week. Further studies in more demonstrating a small reduction in withdrawal symptoms
diverse settings are required. on the AWQ for those randomised to mirtazapine, while
In men who have sex with men, the antidepressant mir- the other demonstrated no difference in withdrawal symp-
tazapine reduced MA use and high-risk sexual behaviours, toms on the Amphetamine Cessation Symptoms Assessment
despite low medication adherence rates [30]. In another (ACSA) [73]. The authors concluded that no medication was
study published by this group since our search, 120 cisgen- demonstrated to be effective in reducing AMPH withdrawal
der males and transgender females who had sex with men symptoms [73].
and had MA use disorder were randomly assigned to mir- Our review also identified several other studies pub-
tazapine 30 mg or placebo OD for 24 weeks with a further lished since the Cochrane Review reporting on withdrawal.
12 weeks’ follow-up [71]. The primary outcome was MA- In studies reviewed here examining withdrawal symptoms,
positive urines and secondary outcomes were sexual risk no pharmacotherapy yielded robustly convincing results,
behaviours. Results were replicated, with reductions in both while some had marked limitations; for example, in a recent
MA use and, although to a lesser extent than the first study Iranian study of riluzole (n = 74) [34], secondary outcomes
and only at week 24, high-risk sexual behaviours (unpro- included the AWQ [67]; however, it excluded any partici-
tected anal sex, number of partners) in participants ran- pants who smoked cigarettes more than 3 days per week,
domised to mirtazapine as compared with placebo. Adher- severely limiting its generalisability to stimulant consumers
ence was still imperfect, with an average of 28.1–39.5% more broadly. Overall, the studies we reviewed signalled
medication adherence between the two arms. Participants some potential promise in agonist therapy (dexampheta-
received concomitant psychosocial therapy, and the authors mine), CRF1 antagonist therapy (pexacerfont) and gluta-
suggest that mirtazapine may be a useful adjunct to psycho- matergic agents (riluzole) as potential pharmacotherapy can-
social therapy, but only in the examined population. didates for MA withdrawal; however, further larger studies
There are currently other ongoing (recruiting) pharmaco- in the withdrawal context are required.
therapy studies for AMPH/MA dependence. These include Although there are no evidence-based pharmacotherapies
a double-blind placebo-controlled study of NAC (1200 mg for AMPH/MA withdrawal [74], standard of care generally
po BD) in outpatients over 12 weeks [72] currently recruit- includes symptomatic medications that target symptoms of
ing in Australia. A phase I study examining the safety of withdrawal, including short-term use of benzodiazepines
ascending doses of pomaglumetad (an mGlutamate 2, 3 ago- (e.g. diazepam) for anxiety, agitation and sleep disturbances,
nist) in 24 non-treatment-seeking participants is underway and antipsychotics (e.g. olanzapine) to manage any comor-
in the USA (Heinzerling et al.; ClinicalTrials.gov identifier: bid psychotic symptoms [74]. Research is required on phar-
NCT03106571). A monoclonal antibody (IXT-m200) is macotherapy of stimulant withdrawal.
being investigated in a randomised, placebo-controlled study
as a single dose followed by four MA ‘challenge doses’ for 4.4 Treatment Setting
its effects on the pharmacokinetics of MA and implications
for its effects on drug liking (Ward et al.; ClinicalTrials.gov The majority of studies we reviewed were in the outpatient
identifier: NCT03336866). setting (n = 32, 74.4%), while a minority were conducted in
inpatient settings (n = 5, 11.6%) and the rest were mixed or
4.3 Treatment of Withdrawal Symptoms did not state the setting.
No study we reviewed directly compared outcomes
It should be noted that our search strategy did not seek to between outpatient- and inpatient-treated participants.
identify studies that were specifically for the treatment of Importantly, we did not find any evidence that either
treatment setting is superior to another for any of the out- [79] and possibly more amongst treatment seekers. Forty-
comes we assessed. Hence, we suggest that criteria for the two percent of individuals who had used MA in the prior
selection of treatment setting are based on clinical judge- 12 months also reported being diagnosed or treated for a
ment and resources. For example, when managing stimu- concurrent mental illness—three times as high as the non-
lant withdrawal, the likelihood of severe complications (e.g. illicit drug-using population [80]. Among MA users, the
potential for severe psychiatric and cardiovascular complica- majority report a lifetime prevalence of depression and anxi-
tions during AMPH/MA withdrawal) may favour a period of ety [81]. The exclusion of relatively common comorbidities
inpatient treatment, whereas most AMPH/MA withdrawals such as polydrug dependence and mental health comor-
could safely be completed in an ambulatory setting. Like- bidities limits the generalisability of many of the studies.
wise, significant comorbidity (e.g. psychoses) may impact For example, the role of antipsychotic and antidepressant
the ability to remain in ambulatory care during periods of medications may differ in patients presenting with psycho-
treatment for AMPH/MA withdrawal or treatment. Other sis or depression. Similarly, dependence to other substances
substance use and social environments will also feature such as alcohol, benzodiazepines or opioids is also likely to
when determining the best setting for clinical care [75]. impact upon the safety and efficacy and choice of medica-
Similarly, the choice between residential or ambulatory tions. Medications such as topiramate and naltrexone may be
treatment settings for longer term rehabilitation programmes worth further examination in patients with comorbid alco-
may be determined by factors such as social supports, hous- hol use, whereas the role of naltrexone will vary accord-
ing, employment and legal status of the patient. ing to opioid status; for example, responding to stimulant
use in patients enrolled in opioid agonist treatment. Other
4.5 Specific Populations comorbidities that continue to be poorly addressed include
the management of patients with stimulant dependence and
Nearly a quarter of the reviewed studies had no female par- comorbid attention-deficit hyperactivity disorder (ADHD).
ticipants, and male sex made up over 70% of the popula- Accurate diagnoses of ADHD in the context of AMPH/MA
tion across all studies. In nine of the studies reviewed here use can be complicated [82], and there may be differential
(20.9%), women were excluded by design. In some cases, effects of medications in patients with both conditions. More
this was due to the setting (e.g. male-only residential treat- research is required regarding pharmacological responses for
ment centres), or studies conducted in specific populations patients with ADHD and stimulant use disorders. Another
(e.g. men who have sex with men), and in others the reason key area that has not been adequately addressed in clinical
is not clearly stated. Research suggests women who take trials is the issue of comorbid sleep disturbances in patients
stimulants are more likely to become dependent consum- using AMPH/MA, and the likely impact upon the role of
ers than men who take stimulants [77]. While women are different medications.
underrepresented in the reviewed studies as a proportion of The studies reviewed here report on a variety of outcomes
the population overall, they may not be underrepresented defined, measured and analysed differently across most pub-
as a proportion of the population who present for treat- lications. The broad selection of outcomes and measures
ment. For example, in the US, the setting of over half of render it difficult to meta-analyse or otherwise collectively
the studies reviewed here, only 36% of people estimated to synthesise the study results as reported. Future endeavours
have accessed treatment for illicit drug use in 2016 were to standardise outcome measures across clinical trials in
female [77, 78].Women are more likely to encounter bar- addiction medicine would make it easier to interpret study
riers to alcohol and other drug treatment than men, which results collectively and better translate research results to
may explain why they are under-represented in the studies clinical practice. Importantly, only three studies reviewed
reviewed here. This is due in large part to fear of losing here (7%) provided information on adverse events/seri-
access to children (e.g. due to mandatory reporting), and ous adverse events, despite the standard reporting format
family responsibilities (lack of alternate options for child- adopted by most publishers (CONSORT [83]) including a
care, etc.); women are also more likely to encounter eco- minimum standard of harm reporting. This limits the capac-
nomic barriers to treatment access than are men [76]. ity to appropriately assess the risk versus benefit of the phar-
macotherapies reviewed here. We elected to include studies
4.6 Limitations in this review irrespective of safety reporting, to provide a
comprehensive review of the current status of research.
Seventy-nine percent of the reviewed studies excluded par- Although adherence was reported in most of the studies
ticipants with comorbid mental health diagnoses or con- reviewed here, the methods and definitions were discordant
comitant medications prescribed for comorbid mental health across studies. Adherence thresholds varied and were often
diagnoses. Research suggests that transient psychotic symp- arbitrary. When plasma was assessed for active study drug/
toms are observed in up to 40% of MA-using populations metabolite, there was no measurable metabolite included
in the placebo, and the control data is therefore missing. Finally, because of the similarities in chemical structure
Furthermore, presence of the study drug/metabolite does not and behavioural, psychological and physical effects of AMPH
necessarily indicate adherent consumption of the study drug, and MA [84], we have included studies of AMPH and MA,
and authors varied in their assessments in that regard (i.e. and studies that did not distinguish between AMPH and MA.
present or not versus present at a defined level). Studies rely- MA and AMPH may be knowingly or unknowingly consumed
ing on pill count or self-report lacked critical appraisal of or co-consumed in uncertain concentrations, with variability
the results. For example, in one study where no participant over time and place. However, there is little data on which to
returned un-used study drug, 100% adherence was inferred assess whether there are distinct differences in use disorders
as opposed to examining if there were other reasons (e.g. due to these two substances; further assessment is required.
discarding drug).
Definitions of efficacy of pharmacotherapies vary exten- 4.7 Future Directions
sively. While some studies define success by abstinence from
AMPH/MA, others consider a reduction in use to be a meas- Future research should address small sample sizes and low
ure of treatment success. Abstinence as an outcome can be participant retention and treatment adherence rates, leading
determined by self-report, or by negative UDS at time points to underpowered studies lacking meaningful results. Under-
pre-determined (see Table 5). The desired goal of pharmaco- powered results can be avoided by planning recruitment for
therapy will likely vary depending on the patient, and must high attrition rates, collaborating on multi-centre research,
be patient-focused and clinically relevant. potentially through clinical research networks, and a greater
Disparate criteria were also used when determining eli- role for consumer and clinician engagement in the planning
gibility for a study; for example, the definition of ‘low-use’ and establishment of trials. Medication adherence also needs
(AMPH/MA) in the studies reviewed here was 5 days, 10 days to be better examined and monitored in trials, particularly
and 18 days of the past 30 in various studies. This is an impor- when using medications with abuse liability (e.g. psychoac-
tant limitation in synthesising data and results, and establish- tive medications such as stimulants).
ment of a clinically meaningful cut-off for regular and frequent Populations under-represented in the literature must also
use is imperative. Studies that analysed results by baseline fre- be addressed in future research. Harmonisation of outcomes
quency of MA/AMPH use often grouped days of use into cate- and outcome measures to produce results that can be synthe-
gories defined as ‘light use’ or ‘heavy use’. However, rationale sised by meta-analyses should be a sector-wide imperative,
for cut-points was often missing or ill-defined. In one study, to ensure better research synthesis. At a minimum, reduc-
consumption of MA was classified as ‘heavy use’ among par- tion in MA/AMPH use (e.g. days used or reduction in MA/
ticipants providing three MA-positive UDS/fortnight, while in AMPH-positive UDS) is required for assessment of efficacy.
another study, ‘heavy use’ was classified as self-reported use of The reliance on extended periods of ‘abstinence’ as a pri-
18 days of the prior 30. In a 2007 paper, Hillhouse et al. [19] mary endpoint does not always reflect participant treatment
found that frequency of MA use prior to treatment predicted goals and is a somewhat insensitive marker of clinically
both treatment performance and outcomes following treatment meaningful change in substance use. However, further work
in a psychosocial intervention for MA dependence, reporting is required to determine outcomes that are both clinically
that participants with baseline use of < 15 days in the 30 days meaningful and meaningful to consumers.
prior to intake had better outcomes. Therefore, the disparity Future research should address the need to understand the
in groupings in pharmacotherapy research across studies and influence of co-existing conditions (e.g. ADHD, depression,
drugs makes it difficult to reliably recommend a strategy for comorbid substance use [e.g. tobacco, alcohol, opioids, ben-
determining cut-points. Further research and debate in this area zodiazepines], psychosis, sleep disorders, complex trauma),
is required to determine a clinically meaningful way of group- increasing the likelihood of generating results that can be
ing frequency of use. generalised to participants with comorbid conditions con-
Studies conducted in (e.g. men who have sex with men) sistent with the underlying population.
or excluding (e.g. women) specific populations are limited in Studies examining the efficacy of pharmacotherapy alone
their ability to generalise to other populations. The implica- versus combined medication and psychosocial counselling are
tions of contextual influences on outcomes are unknown. For required to better understand the role each treatment modality
example, no study we reviewed here assessed specific popu- may have. Provision of client-centred care requires future work
lations such as indigenous peoples. Similarly, while women to address the need to better understand concepts of treatment
were often excluded by the study design, no study examined matching or stepped care. Not all patients may need or benefit
only women. It is unknown how generalisable any of the from the same approach. Further, treatments may differ by dose
results reviewed here are outside of the context in which and frequency (intensity) of use. Irrespective of the promise of
they were conducted, and it is unwise therefore to combine pharmacotherapy, effective treatment of substance use disorders
results across populations. requires comprehensive biopsychosocial intervention.
5 Conclusions 4. Silber BY, Croft RJ, Papafotiou K, Stough C. The acute effects of
d-amphetamine and methamphetamine on attention and psycho-
motor performance. Psychopharmacology. 2006;187(2):154–69.
While there are promising candidates, no pharmacotherapy 5. Haber P, Day C, Farrell M, editors. Addiction medicine: princi-
for the treatment of AMPH/MA dependence/use disorder ples and practice. Research: IP Communications, Pty. Ltd; 2015.
has provided convincing results. Studies are often limited 6. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders (DSM-V). 5th ed. Washington:
by small sample sizes in defined populations, and with low American Psychiatric Association; 2016.
treatment retention or completion rates. Different treatment 7. American Psychiatric Association. Diagnostic and statistical
options may be indicated for various degrees of severity of manual of mental disorders (DSM-IV). 4th ed. Washington:
disorder. Combination therapies are yet to be explored. Opti- American Psychiatric Association; 1994.
8. World Health Organization. ICD-10: International statistical clas-
mal psychosocial interventions accompanying medication sification of diseases and related health problems: 10th rev. 2nd
must also be considered. Further and substantial investment ed. Geneva: World Health Organisation; 2004.
to determine effective pharmacotherapies is required. 9. World Health Organization. ICD-11: International classifica-
tion of diseases for mortality and morbidity statistics: 11th rev.
Acknowledgements The authors wish to thank Duncan Graham and Geneva: World Health Organisation; 2018.
Kelly Siefried for reviewing the manuscript; and Lucette Cysique for 10. Farrell M, Martin NK, Stockings E, Borquez A, Cepeda JA,
earlier work related to this review. Degenhardt L, et al. Responding to global stimulant use: chal-
lenges and opportunities. Lancet. 2019;394(10209):1652–67.
11. Karila L, Petit A, Cottencin O, Reynaud M. Methamphetamine
Author Contributions NL had the idea for this systematic review; KJS,
dependence: consequences and complications. Presse Med.
LSA, NL, and NE designed the study; KJS and LSA performed the
2010;39(12):1246–53.
literature search and data analyses; KJS drafted the first manuscript;
12. Chomchai C, Chomchai S. Global patterns of methamphetamine
LSA, NL and NE critically revised the manuscript.
use. Curr Opin Psychiatry. 2015;28(4):269–74.
13. United Nations Office on Drugs and Crime. Treatment of stimu-
Compliance with Ethical Standards lant use disorder: Current practices and promising perspectives.
Vienna: United Nations Office on Drugs and Crime; 2019.
Funding This study was supported by the National Centre for Clini- 14. Lee NK, Rawson RA. A systematic review of cognitive and
cal Research on Emerging Drugs (NCCRED). NCCRED is funded by behavioural therapies for methamphetamine dependence. Drug
the Australian Government Department of Health. NCCRED paid the Alcohol Rev. 2008;27(3):309–17.
open access fee. 15. Harada T, Tsutomi H, Mori R, Wilson DB. Cognitive-behav-
ioural treatment for amphetamine-type stimulants (ATS)-use
disorders. Cochrane Database Syst Rev. 2018;12:cd011315.
Conflicts of Interest KJS has no conflicts to declare. LSA has no con- 16. Shoptaw S, Reback CJ, Peck JA, Yang X, Rotheram-Fuller E,
flicts to declare. NL has received research funding from Camurus, and Larkins S, et al. Behavioral treatment approaches for metham-
has served on Advisory Boards for Mundipharma, Camurus and Indi- phetamine dependence and HIV-related sexual risk behaviors
vior. NE has no conflicts to declare. among urban gay and bisexual men. Drug Alcohol Depend.
2005;78(2):125–34.
Open Access This article is licensed under a Creative Commons Attri- 17. De Crescenzo F, Ciabattini M, D’Alò GL, De Giorgi R, Del Gio-
bution-NonCommercial 4.0 International License, which permits any vane C, Cassar C, et al. Comparative efficacy and acceptability
non-commercial use, sharing, adaptation, distribution and reproduction of psychosocial interventions for individuals with cocaine and
in any medium or format, as long as you give appropriate credit to the amphetamine addiction: A systematic review and network meta-
original author(s) and the source, provide a link to the Creative Com- analysis. PLoS Med. 2018;15(12):e1002715.
mons licence, and indicate if changes were made. The images or other 18. Rawson RA, McCann MJ, Flammino F, Shoptaw S, Miotto K,
third party material in this article are included in the article’s Creative Reiber C, et al. A comparison of contingency management and
Commons licence, unless indicated otherwise in a credit line to the cognitive-behavioral approaches for stimulant-dependent indi-
material. If material is not included in the article’s Creative Commons viduals. Addiction. 2006;101(2):267–74.
licence and your intended use is not permitted by statutory regula- 19. Hillhouse MP, Marinelli-Casey P, Gonzales R, Ang A, Rawson RA.
tion or exceeds the permitted use, you will need to obtain permission Predicting in-treatment performance and post-treatment outcomes
directly from the copyright holder. To view a copy of this licence, visit in methamphetamine users. Addiction. 2007;102(Suppl 1):84–95.
http://creativecommons.org/licenses/by-nc/4.0/. 20. McKetin R, Najman JM, Baker AL, Lubman DI, Dawe S, Ali
R, et al. Evaluating the impact of community-based treatment
options on methamphetamine use: findings from the metham-
phetamine treatment evaluation study (MATES). Addiction.
References 2012;107(11):1998–2008.
21. United Nations Office on Drugs and Crime (UNODC). Termi-
1. World Drug Report 2019 (United Nations publication, Sales No. nology and Information on Drugs. 3rd ed. New York: United
E.19.XI.9). Nations; 2016.
2. Stoneburg D, Shukla R, Magness M. Global methampheta- 22. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA
mine trends: an evolving problem. Int Crim Justice Rev. Group. Preferred reporting items for systematic reviews
2018;28(2):136–61. and meta-analyses: the PRISMA statement. PLoS Med.
3. Meredith CW, Jaffe C, Ang-Lee K, Saxon AJ. Implications of 2009;6(7):e1000097.
chronic methamphetamine use: a literature review. Harv Rev 23. Covidence systematic review software, Veritas Health Innova-
Psychiat. 2005;13(3):141–54. tion, Melbourne, Australia. www.covidence.org.
24. Ahmadi J, Razeghian Jahromi L. Comparing the effect of 41. Heinzerling KG, Swanson AN, Hall TM, Yi Y, Wu Y, Shop-
buprenorphine and methadone in the reduction of methampheta- taw SJ. Randomized, placebo-controlled trial of bupropion in
mine craving: a randomized clinical trial. Trials. 2017;18(1):259. methamphetamine-dependent participants with less than daily
25. Anderson AL, Li SH, Biswas K, McSherry F, Holmes T, Itur- methamphetamine use. Addiction. 2014;109(11):1878–86.
riaga E, et al. Modafinil for the treatment of methamphetamine 42. Jayaram-Lindström N, Hammarberg A, Beck O, Franck J.
dependence. Drug Alcohol Depend. 2012;120(1–3):135–41. Naltrexone for the treatment of amphetamine dependence:
26. Anderson AL, Li SH, Markova D, Holmes TH, Chiang N, a randomized, placebo-controlled trial. Am J Psychiatry.
Kahn R, et al. Bupropion for the treatment of methampheta- 2008;165(11):1442–8.
mine dependence in non-daily users: a randomized, dou- 43. Jittiwutikan J, Srisurapanont M, Jarusuraisin N. Amineptine
ble-blind, placebo-controlled trial. Drug Alcohol Depend. in the treatment of amphetamine withdrawal: a placebo-con-
2015;150:170–4. trolled, randomised, double-blind study. J Med Assoc Thai.
27. Briones M, Shoptaw S, Cook R, Worley M, Swanson AN, Moody 1997;80(9):587–92.
DE, et al. Varenicline treatment for methamphetamine depend- 44. Johnson BA, Ait-Daoud N, Elkashef AM, Smith EV, Kahn R,
ence: a randomized, double-blind phase II clinical trial. Drug Vocci F, et al. A preliminary randomized, double-blind, placebo-
Alcohol Depend. 2018;189:30–6. controlled study of the safety and efficacy of ondansetron in the
28. Coffin PO, Santos GM, Das M, Santos DM, Huffaker S, Mathe- treatment of methamphetamine dependence. Int J Neuropsychop-
son T, et al. Aripiprazole for the treatment of methamphetamine harmacol. 2008;11(1):1–14.
dependence: a randomized, double-blind, placebo-controlled 45. Kohno M, Dennis LE, McCready H, Schwartz DL, Hoffman WF,
trial. Addiction. 2013;108(4):751–61. Korthuis PT. A preliminary randomized clinical trial of naltrex-
29. Coffin PO, Santos GM, Hern J, Vittinghoff E, Santos D, Mathe- one reduces striatal resting state functional connectivity in peo-
son T, et al. Extended-release naltrexone for methamphetamine ple with methamphetamine use disorder. Drug Alcohol Depend.
dependence among men who have sex with men: a randomized 2018;192:186–92.
placebo-controlled trial. Addiction. 2018;113(2):268–78. 46. Kongsakon R, Papadopoulos KI, Saguansiritham R. Mirtazapine
30. Colfax GN, Santos GM, Das M, Santos DM, Matheson T, in amphetamine detoxification: a placebo-controlled pilot study.
Gasper J, et al. Mirtazapine to reduce methamphetamine Int Clin Psychopharmacol. 2005;20(5):253–6.
use: a randomized controlled trial. Arch Gen Psychiatry. 47. Lee N, Pennay A, Hester R, McKetin R, Nielsen S, Ferris J.
2011;68(11):1168–75. A pilot randomised controlled trial of modafinil during acute
31. Cruickshank CC, Montebello ME, Dyer KR, Quigley A, Blaszc- methamphetamine withdrawal: feasibility, tolerability and clini-
zyk J, Tomkins S, et al. A placebo-controlled trial of mirtazap- cal outcomes. Drug Alcohol Rev. 2013;32(1):88–95.
ine for the management of methamphetamine withdrawal. Drug 48. Ling W, Chang L, Hillhouse M, Ang A, Striebel J, Jenkins J,
Alcohol Rev. 2008;27(3):326–33. et al. Sustained-release methylphenidate in a randomized trial
32. Elkashef A, Kahn R, Yu E, Iturriaga E, Li SH, Anderson A, of treatment of methamphetamine use disorder. Addiction.
et al. Topiramate for the treatment of methamphetamine 2014;109(9):1489–500.
addiction: a multi-center placebo-controlled trial. Addiction. 49. Ling W, Shoptaw S, Hillhouse M, Bholat MA, Charuvastra C,
2012;107(7):1297–306. Heinzerling K, et al. Double-blind placebo-controlled evaluation
33. Elkashef AM, Rawson RA, Anderson AL, Li SH, Holmes T, of the PROMETA protocol for methamphetamine dependence.
Smith EV, et al. Bupropion for the treatment of methamphetamine Addiction. 2012;107(2):361–9.
dependence. Neuropsychopharmacology. 2008;33(5):1162–70. 50. Longo M, Wickes W, Smout M, Harrison S, Cahill S, White JM.
34. Farahzadi MH, Moazen-Zadeh E, Razaghi E, Zarrindast MR, Randomized controlled trial of dexamphetamine maintenance
Bidaki R, Akhondzadeh S. Riluzole for treatment of men for the treatment of methamphetamine dependence. Addiction.
with methamphetamine dependence: a randomized, double- 2010;105(1):146–54.
blind, placebo-controlled clinical trial. J Psychopharmacol. 51. Miles SW, Sheridan J, Russell B, Kydd R, Wheeler A, Walters C,
2019;33(3):305–15. et al. Extended-release methylphenidate for treatment of amphet-
35. Galloway GP, Buscemi R, Coyle JR, Flower K, Siegrist JD, Fiske amine/methamphetamine dependence: a randomized, double-
LA, et al. A randomized, placebo-controlled trial of sustained- blind, placebo-controlled trial. Addiction. 2013;108(7):1279–86.
release dextroamphetamine for treatment of methamphetamine 52. Morabbi MJ, Razaghi E, Moazen-Zadeh E, Safi-Aghdam
addiction. Clin Pharmacol Therapeutics. 2011;89(2):276–82. H, Zarrindast MR, Vousoghi N, et al. Pexacerfont as a CRF1
36. Galloway GP, Newmeyer J, Knapp T, Stalcup SA, Smith D. antagonist for the treatment of withdrawal symptoms in men with
Imipramine for the treatment of cocaine and methamphetamine heroin/methamphetamine dependence: a randomized, double-
dependence. J Addict Dis. 1994;13(4):201–16. blind, placebo-controlled clinical trial. Int Clin Psychopharma-
37. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo- col. 2018;33(2):111–9.
controlled study of N-acetyl cysteine plus naltrexone for 53. Mousavi SG, Sharbafchi MR, Salehi M, Peykanpour M, Karim-
methamphetamine dependence. Eur Neuropsychopharmacol. ian Sichani N, Maracy M. The efficacy of N-acetylcysteine in the
2010;20(11):823–8. treatment of methamphetamine dependence: a double-blind con-
38. Heinzerling KG, Swanson AN, Kim S, Cederblom L, Moe A, trolled, crossover study. Arch Iranian Med. 2015;18(1):28–33.
Ling W, et al. Randomized, double-blind, placebo-controlled trial 54. Rezaei F, Emami M, Zahed S, Morabbi MJ, Farahzadi M,
of modafinil for the treatment of methamphetamine dependence. Akhondzadeh S. Sustained-release methylphenidate in metham-
Drug Alcohol Depend. 2010;109(1–3):20–9. phetamine dependence treatment: a double-blind and placebo-
39. Heinzerling KG, Gadzhyan J, van Oudheusden H, Rodriguez F, controlled trial. Daru. 2015;23:2.
McCracken J, Shoptaw S. Pilot randomized trial of bupropion 55. Rezaei F, Ghaderi E, Mardani R, Hamidi S, Hassanzadeh K.
for adolescent methamphetamine abuse/dependence. J Adolesc Topiramate for the management of methamphetamine depend-
Health. 2013;52(4):502–5. ence: a pilot randomized, double-blind, placebo-controlled trial.
40. Heinzerling KG, Shoptaw S, Peck JA, Yang X, Liu J, Roll J, et al. Fundam Clin Pharmacol. 2016;30(3):282–9.
Randomized, placebo-controlled trial of baclofen and gabapentin 56. Runarsdottir V, Hansdottir I, Tyrfingsson T, Einarsson M,
for the treatment of methamphetamine dependence. Drug Alco- Dugosh K, Royer-Malvestuto C, et al. Extended-release injecta-
hol Depend. 2006;85(3):177–84. ble naltrexone (XR-NTX) with intensive psychosocial therapy for
amphetamine-dependent persons seeking treatment: a placebo- 74. Wodarz N, Krampe-Scheidler A, Christ M, Fleischmann H,
controlled trial. J Addict Med. 2017;11(3):197–204. Looser W, Schoett K, et al. Evidence-based guidelines for the
57. Salehi M, Emadossadat A, Kheirabadi GR, Maracy MR, Shar- pharmacological management of acute methamphetamine-related
bafchi MR. The effect of buprenorphine on methamphetamine disorders and toxicity. Pharmacopsychiatry. 2017;50(3):87–95.
cravings. J Clinical Psychopharmacol. 2015;35(6):724–7. 75. Lintzeris N, Sunjic S, Demirkol A, Branezac M, Ezard N,
58. Schottenfeld RS, Chawarski MC, Sofuoglu M, Chooi WT, Zaha- Siefried K, et al. Management of withdrawal from alcohol and
rim NM, Yasmin M, et al. Atomoxetine for amphetamine-type other drugs: an evidence check rapid review brokered by the
stimulant dependence during buprenorphine treatment: a rand- Sax Institute for the NSW Ministry of Health. Sydney: The Sax
omized controlled trial. Drug Alcohol Depend. 2018;186:130–7. Institute; 2019.
59. Shearer J, Darke S, Rodgers C, Slade T, van Beek I, Lewis 76. Green CA. Gender and use of substance abuse treatment services.
J, et al. A double-blind, placebo-controlled trial of modafinil Alcohol Res Health. 2006;29(1):55–62.
(200 mg/day) for methamphetamine dependence. Addiction. 77. National Institute on Drug Abuse (NIDA). Substance use in
2009;104(2):224–33. women. 2020.
60. Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Steward T, 78. Center for Behavioral Health Statistics and Quality. Results from
Wang J, Swanson AN, et al. Randomized, placebo-controlled the 2016 national survey on drug use and health: detailed tables.
trial of bupropion for the treatment of methamphetamine depend- Rockville: Substance Abuse and Mental Health Services Admin-
ence. Drug Alcohol Depend. 2008;96(3):222–32. istration; 2017.
61. Shoptaw S, Huber A, Peck J, Yang X, Liu J, Jeff D, et al. Ran- 79. Glasner-Edwards S, Mooney LJ. Methamphetamine psy-
domized, placebo-controlled trial of sertraline and contingency chosis: epidemiology and management. CNS Drugs.
management for the treatment of methamphetamine dependence. 2014;28(12):1115–26.
Drug Alcohol Depend. 2006;85(1):12–8. 80. Australian Institute of Health and Welfare. National drug strategy
62. Sulaiman AH, Gill JS, Said MA, Zainal NZ, Hussein HM, Guan household survey 2016: detailed findings. Canberra: Australian
NC. A randomized, placebo-controlled trial of aripiprazole for Institute of Health and Welfare; 2017.
the treatment of methamphetamine dependence and associated 81. Darke S, Kaye S, McKetin R, Duflou J. Major physical and psy-
psychosis. Int J Psychiatry Clin Pract. 2013;17(2):131–8. chological harms of methamphetamine use. Drug Alcohol Rev.
63. Tiihonen J, Krupitsky E, Verbitskaya E, Blokhina E, Mamontova 2008;27(3):253–62.
O, Fohr J, et al. Naltrexone implant for the treatment of poly- 82. Clemow DB, Walker DJ. The potential for misuse and
drug dependence: a randomized controlled trial. Am J Psychiatry. abuse of medications in ADHD: a review. Postgrad Med.
2012;169(5):531–6. 2014;126(5):64–81.
64. Tiihonen J, Kuoppasalmi K, Fohr J, Tuomola P, Kuikanmaki O, Vorma 83. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement:
H, et al. A comparison of aripiprazole, methylphenidate, and placebo updated guidelines for reporting parallel group randomized trials.
for amphetamine dependence. Am J Psychiatry. 2007;164(1):160–2. Ann Intern Med. 2010;152(11):726–32.
65. Urschel HC 3rd, Hanselka LL, Baron M. A controlled trial of 84. Kirkpatrick MG, Gunderson EW, Johanson CE, Levin FR, Fol-
flumazenil and gabapentin for initial treatment of methylam- tin RW, Hart CL. Comparison of intranasal methamphetamine
phetamine dependence. J Psychopharmacol. 2011;25(2):254–62. and d-amphetamine self-administration by humans. Addiction.
66. Winhusen TM, Brigham GS, Kropp F, Lindblad R, Gardin JG 2012;107(4):783–91.
2nd, Penn P, et al. A randomized trial of concurrent smoking- 85. Ceci A, Garattini S, Gobbi M, Mennini T. Effect of long term
cessation and substance use disorder treatment in stimulant- amineptine treatment on pre- and postsynaptic mechanisms in rat
dependent smokers. J Clin Psychiatry. 2014;75(4):336–43. brain. Br J Pharmacol. 1986;88(1):269–75.
67. Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine 86. Ponzio F, Achilli G, Garattini S, Perego C, Sacchetti G, Algeri
withdrawal: I. Reliability, validity and factor structure of a meas- S. Amineptine: its effect on the dopaminergic system of rats. J
ure. Aust NZ J Psychiatry. 1999;33(1):89–93. Pharm Pharmacol. 1986;38(4):301–3.
68. Ezard N, Dunlop A, Hall M, Ali R, McKetin R, Bruno R, et al. 87. APO-Mirtazapine® (mirtazapine) [package insert on the internet].
LiMA: a study protocol for a randomised, double-blind, placebo Apotex Pty Ltd 2019 (cited 2019 June 20). Avaliable from: https
controlled trial of lisdexamfetamine for the treatment of meth- ://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName
amphetamine dependence. BMJ Open. 2018;8(7):e020723. =ProductInfo&searchKeyword=mirtazapine&PreviousPage=~/
69. Ma JZ, Johnson BA, Yu E, Weiss D, McSherry F, Saadvandi J, Search/QuickSearch.aspx&SearchType=&ID=82050001_2.
et al. Fine-grain analysis of the treatment effect of topiramate on 88. Zyban SR® (bupropion) [package insert on the internet]. Aspen
methamphetamine addiction with latent variable analysis. Drug 2017 (cited 2019 June 20). Avaliable from: https://www.mimso
Alcohol Depend. 2013;130(1–3):45–51. nline.com.au/Search/AbbrPI.aspx?ModuleName=ProductInf
70. Gatch MB, Flores E, Forster MJ. Nicotine and methamphetamine o&search Keywo rd=Zyban+ SR&Previo usPag e=~/Search /Quick
share discriminative stimulus effects. Drug Alcohol Depend. Search.aspx&SearchType=&ID=54480001_2.
2008;93(1–2):63–71. 89. APO-Sertraline® (sertraline) [package insert on the internet].
71. Coffin PO, Santos GM, Hern J, Vittinghoff E, Walker JE, Mathe- Apotex Pty Ltd 2017 (cited 2019 June 20). Avaliable from: https
son T, et al. Effects of mirtazapine for methamphetamine use ://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName
disorder among cisgender men and transgender women who have =ProductInfo&searchKeyword=APO-Sertraline&PreviousPa
sex with men: a placebo-controlled randomized clinical trial. ge=~/Search /QuickS earch .aspx&Search Type= &ID=11540
JAMA Psychiatry. 2020;77(3):246–55. 001_2.
72. McKetin R, Dean OM, Turner A, Kelly PJ, Quinn B, Lubman 90. APO-Atomoxetine ® (atomoxetine) [package insert on the
DI, et al. A study protocol for the N-ICE trial: a randomised internet]. Apotex Pty Ltd 2018 (cited 2019 June 20). Avali-
double-blind placebo-controlled study of the safety and efficacy able from: https : //www.mimso n line . com.au/Searc h /AbbrP
of N-acetyl-cysteine (NAC) as a pharmacotherapy for metham- I.aspx?Module Name= Produc tInfo &search Keywo rd=APO-Sertr
phetamine (“ice”) dependence. Trials. 2019;20(1):325. aline&PreviousPage=~/Search/QuickSearch.aspx&SearchType
73. Shoptaw SJ, Kao U, Heinzerling K, Ling W. Treatment for =&ID=11540001_2.
amphetamine withdrawal. Cochrane Database Syst Rev. 91. Tofranil® (imipramine) [package insert on the internet]. Amdip-
2009;2:Cd003021. harm Mercury 2019 (cited 2019 June 20). Avaliable from: https
://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName ://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName
=ProductInfo&searchKeyword=Tofranil&PreviousPage=~/ =ProductInfo&searchKeyword=Subutex&PreviousPage=~/
Search/QuickSearch.aspx&SearchType=&ID=5080001_2. Search/QuickSearch.aspx&SearchType=ID=58190001_2.
92. Aripiprazole GH® (aripiprazole) [package insert on the inter- 101. Aspen Methadone Syrup® (methadone) [package insert on the
net]. Generic Health Pty Ltd 2019 (cited 2019 June 20). Avali- internet].Aspen Pharma Pty Ltd 2017 (cited 2019 June 20).
able from: https : //www.mimso n line . com.au/Searc h /AbbrP Avaliable from: https://www.mimsonline.com.au/Search/AbbrP
I.aspx?Modul e Name = Produ c tInf o &searc h Keyw o rd=Aripi I.aspx?Module Name= Produc tInfo &search Keywo rd=Aspen
prazol e+GH&Previo usPag e=~/Search /QuickS earch .aspx&Searc +Metha d one+Syrup & Previ o usPa ge=~/Searc h /Quick S earc
hType=&ID=92340001_2. h.aspx&SearchType=&ID=30830001_2.
93. APO-Topiramate® (topiramate) [package insert on the internet]. 102. APO-Naltrexone® (naltrexone) [package insert on the internet].
Apotex Pty Ltd 2019 (cited 2019 June 20). Avaliable from: https Apotex 2017 (cited 2019 June 20). Avaliable from: https://www.
://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName mimsonline.com.au/Search/AbbrPI.aspx?ModuleName=Produ
=ProductInfo&searchKeyword=APO-Topiramate&PreviousPa ctInfo&searchKeyword=APO-Naltrexone&PreviousPage=~/
ge=~/Search /QuickS earch .aspx&Search Type= &ID=84600 Search/QuickSearch.aspx&SearchType=&ID=46910001_2.
001_2. 103. Chiu CT, Ma T, Ho IK. Attenuation of methamphetamine-
94. Aspen Dexamfetamine® (dexamfetamine) [package insert on induced behavioral sensitization in mice by systemic adminis-
the internet]. Aspen Pharma 2017 (cited 2019 June 20). Avali- tration of naltrexone. Brain Res Bull. 2005;67(1–2):100–9.
able from: https://www.mimsonline.com.au/Search/QuickSearc 104. APO-Ondansetron® (ondansetron) [package insert on the internet].
h.aspx?ModuleName=ProductInfo&searchKeyword=Aspen Arrow 2016 (cited 2019 June 20). Avaliable from: https://www.
+Dexamfetamine. mimsonline.com.au/Search/AbbrPI.aspx?ModuleName=Produ
95. Artige® (methylphenidate) [package insert on the internet]. ctInfo&searchKeyword=APO-Ondansetron&PreviousPage=~/
Novartis 2017 (cited 2019 June 20). Avaliable from: https: //www. Search/QuickSearch.aspx&SearchType=&ID=82630001_2.
mimsonline.com.au/Search/AbbrPI.aspx?ModuleName=Produ 105. Champix® (varenecline) [package insert on the internet]. Pfizer
ctInfo&searchKeyword=Artige&PreviousPage=~/Search/Quick Australia Pty Ltd 2019 (cited 2019 June 20). Avaliable from: https
Search.aspx&SearchType=&ID=123330001_2. ://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName
96. APO-Modafinil® (modafinil) [package insert on the internet]. =ProductInfo&searchKeyword=Champix&PreviousPage=~/
Apotex Pty Ltd 2017 (cited 2019 June 20). Avaliable from: https Search/QuickSearch.aspx&SearchType=&ID=78600001_2.
://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName 106. N-Acetyl-Cysteine (acetylcysteine) [package insert on the
=ProductInfo&searchKeyword=APO-Modafi nil&PreviousPa internet]. BioMedica Neuraceuticals (cited 2019 June 20).
ge=~/Search /QuickS earch .aspx&Search Type= &ID=12142 Avaliable from: https://www.mimsonline.com.au/Search/AbbrP
0001_2. I.aspx?ModuleName=ProductInfo&searchKeyword=N-Acety
97. APO-Baclofen® (baclofen) [package insert on the internet]. Apo- l-Cysteine&PreviousPage=~/Search/QuickSearch.aspx&Searc
tex Pty Ltd 2019 (cited 2019 June 20). Avaliable from: https hType=&ID=128250001_2.
://www.mimsonline.com.au/Search/AbbrPI.aspx?ModuleName 107. APO-Riluzole® (riluzole) [package insert on the internet]. Apo-
=ProductInfo&searchKeyword=APO-Baclofen&PreviousPa tex 2013 (cited 2019 June 20). Avaliable from: https://www.
ge=~/Search /QuickS earch .aspx&Search Type= &ID=12352 mimsonline.com.au/Search/AbbrPI.aspx?ModuleName=Produ
0001_2. ctInfo&searchKeyword=APO-Riluzole&PreviousPage=~/Searc
98. Gabapentin Generichealth® (gabapentin) [package insert on the h/QuickSearch.aspx&SearchType=&ID=96100001_2.
internet]. Generic Health Pty Ltd 2018 (cited 2019 June 20). 108. Koob GF, Volkow ND. Neurobiology of addiction: a neurocir-
Avaliable from: https://www.mimsonline.com.au/Search/AbbrP cuitry analysis. Lancet Psychiatry. 2016;3(8):760–73.
I.aspx?Module Name= Produc tInfo &search Keywo rd=abape 109. Zorrilla EP, Logrip ML, Koob GF. Corticotropin releasing factor:
ntin+Gener i chea l th&Previ o usPa ge=~/Searc h /Quick S earc a key role in the neurobiology of addiction. Front Neuroendo-
h.aspx&SearchType=&ID=124490001_2. crinol. 2014;35(2):234–44.
99. Cousins MS, Roberts DC, de Wit H. GABA(B) receptor agonists 110. Anexate® (Flumazenil) [package insert on the internet]. Phar-
for the treatment of drug addiction: a review of recent findings. maco 2017 (cited 2019 June 20). Avaliable from: https://www.
Drug Alcohol Depend. 2002;65(3):209–20. mimsonline.com.au/Search/AbbrPI.aspx?ModuleName=Produ
100. Subutex® (buprenorphine) [package insert on the internet]. Indi- ctInfo&searchKeyword=Anexate&PreviousPage=~/Search/
vior Pty Ltd 2018 (cited 2019 June 20). Avaliable from: https QuickSearch.aspx&SearchType=&ID=21440001_2.
Affiliations
Krista J. Siefried1,2,3 · Liam S. Acheson2 · Nicholas Lintzeris4,5,6 · Nadine Ezard1,2,3,6
1 4
The National Centre for Clinical Research on Emerging Division of Addiction Medicine, Faculty of Medicine
Drugs (NCCRED), Sydney, NSW, Australia and Health, The University of Sydney, Sydney, NSW,
2 Australia
St Vincent’s Hospital Alcohol and Drug Service,
5
Darlinghurst, 390 Victoria St, 2010 Sydney, NSW, Australia Drug and Alcohol Services, South Eastern Sydney Local
3 Health District, Sydney, NSW, Australia
The University of New South Wales, National Drug
6
and Alcohol Research Centre (NDARC), Sydney, NSW, New South Wales Drug and Alcohol Clinical Research
Australia and Improvement Network (DACRIN), Sydney, NSW,
Australia

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CNS Drugs (2020) 34:337–365

Pharmacological Treatment of Methamphetamine/Amphetamine

Published online: 17 March 2020

1 Introduction [1]. Approximately 29 million people worldwide aged

amphetamines, methamphetamine or methcathinone” [9].

Fig. 1 PRISMA flow diagram

Table 3 Pharmacotherapies reviewed

Tricyclic antidepressants (TCAs)

Central nervous system stimulants

Other central nervous system agents

GABAB agonist/GABAergic agents

Partial cholinergic nicotinic agonist

n Number of reviewed studies investigating this pharmacotherapy

Central nervous system stimulants

col, outpatient, New Zealand and retention. No differences in craving,

(UDS). No differences in measures

to that treatment group (n = 3)

Outcome assessed Measures used Variations on analysis

• 100 mm (point) VAS (n = 5)

Outcome assessed Measures used Variations on analysis

Anxiety (n = 3) Hamilton Rating Scale for Anxiety (HAM-A) (n = 1)

One study (2%) examined sertraline (50 mg po BD),

tically significant differences between arms on secondary

ability by staff and participants.

randomised 69 opioid and ATS-dependent participants to

outcome [58]. The proportion of ATS-negative UDS was

achieved only a small effect size, while there was no statisti-

cally significant difference in days abstinent. For secondary

Barnes Akathisia Scale (BAS) (n = 1)

lower for the atomoxetine arm, while the depression scores

were significantly reduced in the atomoxetine arm compared

Aripiprazole was assessed in two studies on its own [28,

MA dependence and associated psychoses, participants ran-

domised to aripiprazole (5–10 mg po OD) demonstrated no

significant difference in abstinence compared with placebo

[62]. However, those randomised to the aripiprazole arm

strate a decrease on symptom scores for psychopathology on

One 16-week outpatient study of 88 MA-dependent par- 3.4.9 5HT3‑Receptor Antagonist

Krista J. Siefried1,2,3 · Liam S. Acheson2 · Nicholas Lintzeris4,5,6 · Nadine Ezard1,2,3,6

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One 16-week outpatient study of 88 MA-dependent par- 3.4.9 5HT3‑Receptor Antagonist