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Expert Review of Clinical Pharmacology

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Pharmacological treatments formethamphetamine addiction: current status andfuture directions

Javier Ballester, Gerald Valentine & Mehmet Sofuoglu

To cite this article: Javier Ballester, Gerald Valentine & Mehmet Sofuoglu (2017) Pharmacologicaltreatments for methamphetamine addiction: current status and future directions, Expert Review ofClinical Pharmacology, 10:3, 305-314, DOI: 10.1080/17512433.2017.1268916

To link to this article: https://doi.org/10.1080/17512433.2017.1268916

Accepted author version posted online: 07Dec 2016.Published online: 20 Dec 2016.

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REVIEW

Pharmacological treatments for methamphetamine addiction: current status andfuture directionsJavier Ballestera,b, Gerald Valentinea,b and Mehmet Sofuoglua,b

aDepartment of Psychiatry, Yale School of Medicine, New Haven, CT, USA; bVA Connecticut Healthcare System, West Haven, CT, USA

ABSTRACTIntroduction: Methamphetamine (MA) abuse remains a global health challenge despite intenseresearch interest in the development of pharmacological treatments. This review provides a summaryof clinical trials and human studies on the pharmacotherapy of methamphetamine use disorder (MUD).Areas covered: We summarize published clinical trials that tested candidate medications for MUD andalso conducted PubMed and Google Scholar searches to identify recently completed clinical trials usingthe keywords ‘methamphetamine’ ‘addiction’ ‘pharmacotherapy’ and ‘clinical trial.’ To determine thestatus of ongoing clinical trials targeting MUD, we also searched the ClinicalTrials.gov online database.We conclude this review with a discussion of current research gaps and future directions.Expert commentary: Clinical trials examining the potential for pharmacotherapies of MUD have largelybeen negative. Future studies need to address several limitations to reduce the possibility of Type IIerrors: small sample sizes, high dropout rates or multiple comorbidities. Additionally, new treatmenttargets, such as MA-induced disruptions in cognition and in the neuroimmune system, merit trials withagents that selectively modulate these processes.

ARTICLE HISTORYReceived 15 August 2016Accepted 1 December 2016

KEYWORDSAddiction; neurobiology;pharmacotherapy; cognition;stimulants

1. Introduction

Methamphetamine (MA) and related stimulants have becomethe world’s second most widely abused drug class after can-nabis, with an estimated 24 million users worldwide [1]. About60% of the MA dependent individuals live in South East Asia,which has seen a steady increase in use over the past decade,and according to 2013 estimates, there are approximately600,000 MA users in the United States [1]. Although amphe-tamines and MA have similar pharmacodynamic effects, MA ismore addictive due to greater CNS penetration and a longerduration of action. MA use is associated with an increased riskof medical problems such as HIV and hepatitis-C infection andmany psychosocial problems including homelessness, unem-ployment, crime, and imprisonment. Other medical risksinclude cerebrovascular events, strokes [2], cardiomyopathyand other cardiovascular problems [3], dental and periodontaldisease [4], and specific complications related to the route ofadministration including airway irritation and vascular infec-tions. In addition, recent studies show that compared to otherpopulations, people with a history of MA use are more likely todevelop Parkinson’s disease later in life [5].

Currently available treatments for methamphetamine usedisorder (MUD) are primarily behavioral and include contin-gency management, 12-step facilitation, cognitive behavioraltherapy, and relapse prevention. Unfortunately, these treat-ments have variable efficacy and are not widely available [6].In addition, effective pharmacological agents for the treat-ment of MUD have not been developed despite ongoing

preclinical and clinical research efforts [7]. Given the significantmedical and social burden resulting from MUD, the develop-ment of effective pharmacological treatments remains a glo-bal public health priority.

This review complements recent systematic reviews of clin-ical trials for MUD [8-10] but extends the scope by highlight-ing emerging pharmacological trials that are using novelapproaches such as cognitive-enhancement strategies andimmunotherapies. We first briefly summarize the epidemiol-ogy and comorbidity of MUD followed by a review of the basicpharmacology and toxicology of MA. We then summarizecompleted double blind clinical trials for MUD (Table 1) andhighlight ongoing studies in humans with innovative pharma-cological targets (Table 2). We conclude with a discussion ofcurrent research gaps, future directions and an expert opinion.

2. Methods

We conducted PubMed and Google Scholar searches to iden-tify different classes of medication that have been examinedfor the treatment of MUD. The keywords were ‘methamphe-tamine,’ ‘addiction,’ ‘pharmacotherapy’ and ‘clinical trial.’Inclusion criteria included those studies that were written inEnglish between 2000 and 2016, and studies using a doubleblind, placebo controlled study design (Table 1). To identifymore recent unpublished and ongoing studies, we searchedthe ClinicalTrials.gov database using the same keywords(Table 2).

CONTACT Javier Ballester javier.ballester@yale.edu VA Connecticut Healthcare System 950 Campbell Avenue, 151D, West Haven, 06516 CT, USA

EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2017VOL. 10, NO. 3, 305–314http://dx.doi.org/10.1080/17512433.2017.1268916

© 2016 Informa UK Limited, trading as Taylor & Francis Group

Table1.

Pharmacolog

icalclinicaltrialsin

methamph

etam

ineusedisorder.

Medication

Subjects

Type

ofstud

yTreatm

ent

Primaryou

tcom

eResults

Authors

Antid

epressants

Buprop

ion(DNRI)

100bu

prop

ion

104placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

12-weeks

150mgBID

MAuse(urin

e)Nodiffe

rences.

Anderson

etal.[11]

Mirtazapine(NAS

SA)

30mirtazapine

30placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

12-weeks

30mgdaily

MAuse(urin

e)Redu

ctionin

MAuse.

Colfaxet

al.[12]

Imipramine(TCA

)22

imipramine

10placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

180days

150mgdaily

Retention

Higherretentionwith

imipramine.

Galloway

etal.[13]

Sertraline(SSRI)

120sertraline

109controls

Dou

ble-blindplacebo-controlled

clinicaltrial.

12-weeks

100mgdaily

MAuse(urin

eandself-

repo

rted)

Nodiffe

rences.

Shop

taw

etal.[14]

Agon

isttherapy

Dextroamph

etam

ine

30D-AMP

30placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

8-weeks

60mgdaily

MAuse(urin

e)Nodiffe

rences.

Activegrou

pless

cravingandwith

draw

al.

Galloway

etal.[15]

Methylphenidate

55MPH

-SR

55placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

10-weeks

Finald

ose:54

mgdaily

MAuse(self-repo

rted)

Nodiffe

rences.

Activegrou

pless

useandcravingcompared

tobaseline.

Ling

etal.[16]

Methylphenidate

28MPH

-SR

28placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

10-weeks

Finald

ose:54

mgdaily

Craving

Less

cravingandurinepo

sitivediffe

rent

inweek10.

Rezaei

etal.[17]

Mod

afinil

142mod

afinil

68placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

12-weeks

72–200

mg

70–400

mg

MAuse(urin

e)Nodiffe

rences.

Anderson

etal.[18]

Gabaenhancers

Topiramate

69topiramate

71placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

13-weeks

Finald

ose:200mgdaily

MAuse(urin

e)Nodiffe

rences.

Maet

al.[19]

Baclofen/Gabapentin

25baclofen

26gabapentin

37placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

16-weeks

60mgbaclofen

2400

mggabapentin

MAuse(urin

e)Nodiffe

rences.

Heinzerlinget

al.[20]

Antip

sychotics

Aripiprazole

45aripiprazole

45placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

12-weeks

Finald

ose:20

mgdaily

MAuse(urin

e)Nodiffe

rences.

Coffinet

al.[21]

Glutamate/Opiate

mod

ulators

N-Acetylcysteineplus

Naltrexon

e

14NAC

/Naltrexon

e17

placebo

Dou

ble-blindplacebo-controlled

clinicaltrial.

8-weeks

Finald

oses:2

400mgNAC

/200

mg

Naltrexon

e.Craving

Nodiffe

rences.

Grant

etal.[22]

N-Acetylcysteine

32subjects

initial

23subjects

completed

stud

y

Dou

ble-blindplacebo-controlled

crossover

clinicaltrial.

8-weeks

NAC

1200

mg/day

Craving

Less

craving

Mou

saviSG

etal.[23]

DNRI:d

opam

ineandno

repineph

rinereup

take

inhibitor;NAS

SA:n

oradrenergicandspecificserotonergicantid

epressant;

TCA:

tricyclic

antid

epressant;SSRI:selectiveserotoninreup

take

inhibitor;MA:

methamph

etam

ine.

306 J. BALLESTER ET AL.

3. Epidemiology of MUD

Globally, the prevalence of MA use is relatively high in theUnited States (US), Mexico, China and Thailand, with SouthAsia and the Middle East representing the areas with highestincrease over the past decade [24]. For example, in Iran, MAuse has increased from a point prevalence of 6% in 2008 to44% of drug abusers reporting a use history in 2012 [25]. Inthe United States, an estimated 569,000 people aged 12 orolder are current MA users. This figure is similar to prevalenceestimates made between 2002 and 2013. Although the pre-valence of MA dependence in the US is similar among malesand females, women seem to start using MA earlier than menand are overrepresented in some treatment samples [26–28].The majority of treatment admissions in the US are for non-Hispanic White (69%) individuals followed by those of Mexicanheritage (12%). MA use in the US displays regional variabilitywith a higher prevalence in the West and parts of the mid-West [1].

Individuals with MUD commonly have mental healthcomorbidities and other addictions. For example, the USNational Epidemiologic Survey on Alcohol and RelatedConditions (NESARC) data has shown that among individualswho use MA, the lifetime prevalence of mood and anxiety

disorders was 51% and 39%, respectively [29]. In anothersurvey of a clinical sample (n = 189) with a MUD, 57% hadlifetime dependence on other substances (alcohol 33%,cocaine 27%, cannabis 15%, opioids 12%) [30]. Furthermore,in a recent study from a clinical sample (n = 100) diagnosedwith MA dependence, the prevalence of comorbid psychiatricdisorders was 36%, including mood disorders (16%), psychoticdisorders (13%) and anxiety disorders (7%) [31]. It is importantto highlight that longitudinal studies that might help teaseapart the temporal relationship between these comorbiditieshave not yet been conducted.

4. Pharmacology and toxicity of MA

4.1. Basic pharmacology of MA

The reinforcing effects of MA are thought to be mediated by adrug-induced increase in synaptic dopamine (DA) levels withinthe mesocorticolimbic DA system that principally includes theventral tegmental area DA projection neurons and their pri-mary targets, the nucleus accumbens (NAc) and prefrontalcortex (PFC) [9]. MA also increases synapticnorepinephrine (NE) and serotonin levels. NE release mediatesarousal and cardiovascular activation, as well as stress

Table 2. Ongoing/open label clinical trials/lab studies and novel treatment approaches in methamphetamine use disorder.

Target Agent Mechanism of action ID/type of study Status (year)

Ongoing/Open label clinical trials/Lab studiesSerotonin Buspirone Binds to serotonin type 1A receptors NCT01843205

Phase IRecruiting

Norepinephrine/Dopamine

Lisdexamfetamine Prodrug of dextroamphetamine. Blocks the reuptake andfacilitates the release of dopamine and norepinephrine.

NCT02034201Phase I

Recruiting

Entacapone Inhibitor of catechol-O-methyltransferase NCT02058966Phase 0

Recruiting(Apr 2015)

Doxazosin Alpha-1 receptor blocker NCT02785393Phase I

Completed(Sept 2016)

Prazosin Alpha-1 receptor blocker NCT01178138Phase II

Completed(Sept 2014)

GABA Vigabatrin Inhibits GABA transaminase. NCT00730522Phase II

Terminated(July 2012)

Glutamate Acamprosate Blocks NMDA and perhaps other glutamatergic receptors. NCT00571922Phase II

Completed(March 2016)

Renin-angiotensin

Perindopril/Candesartan Inhibits angiotensin-converting enzyme/Blocks angiotensin-IIreceptor.

NCT01062451Phase I

Recruiting

Combination Oxazepam and Naltrexone Enhances GABA-A receptors. Mu opioid receptor antagonist. NCT01967381Phase 0

Recruiting

Bupropion and Naltrexone Inhibits reuptake of norepinephrine and dopamine. Mu opioidreceptor antagonist.

NCT01982643Phase I

Completed(Jan 2016)

Delayed release Ondansetron andimmediate release Methylphenidate

Ondansetron: 5-HT3 receptor antagonist. NCT01377662Phase II

Completed(Sept 2014)

Novel treatment approachesNootropics Citicoline Intermediate in the generation of phosphatidylcholine from

cholineNCT00950352PhaseIII

Completed(Feb 2015)

Rivastigmine Inhibits acetylcholinesterase and butyrylcholinesterase NCT01073319Phase I

Completed(2012)

Varenicline Partial agonist at α4β2 acetylcholine receptors NCT01365819Phase II

Completed(May 2015)

Atomoxetine Selective norepinephrine Reuptake Inhibitor NCT01557569Phase II

Completed(July 2015)

Glial Cells Ibudilast Phosphodiesterase 4 inhibitor. NCT01860807Phase II

Recruiting

Immunotherapy Ch-mAb7F9 Human-mouse monoclonal chimeric antibody that binds tomethylphenidate

NCT01603147Phase I

Completed(May 2014)

Hormones Oxytocin NCT02881177Phase I

Not yet open(Aug 2016)

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 307

response signaling that may drive stress-induced drug use/relapse [32]. Increased synaptic serotonin levels may enhancesome of the behavioral effects of MA including the develop-ment of addiction [33].

In addition to monoamines, there are other less inten-sively studied neurotransmitters involved in mediating acuteand chronic effects of MA including GABA, glutamate, acet-ylcholine (Ach), corticotropin releasing factor (CRF) andother stress hormones. GABA, the main inhibitory neuro-transmitter in the brain, reduces the reinforcing effects ofstimulants, presumably by modulating the DA release asso-ciated with stimulant drug activity and drug cues [34].Glutamate, the main excitatory neurotransmitter in thebrain, is one of the primary mediators driving sensitizationand craving in response to stimulant drugs [35], and inpreclinical models, glutamate plays an essential role indrug and cue-induced reinstatement [36] suggesting a rolefor glutamate in relapse to drug seeking. In addition, thor-ough its central role in drug-induced neuronal plasticity [37],alterations in glutamatergic signaling may explain otherphenomena such as protracted abstinence [36]. Finally, Achlikely participates in mediating the cognitive-enhancingeffects of MA, including sustained attention [38], and bothacute exposure to MA, and abstinence from MA use, activateCRF and stress-hormone pathways [39].

In addition to neurotransmitters, there is growing evidenceof neuroimmune involvement in the acute and chronic effectsof MA [40]. In preclinical studies, MA exposure is associatedwith activation of microglia and astrocytes [41], and disruptionof blood–brain barrier integrity [42]. For example, in a recentpreclinical study of stimulants such as cocaine, the acutereinforcing action required activation of the Toll-like receptor4 (TLR4) located on microglia [43]. TLR4 is involved in immunesurveillance of pathogens, endogenous danger signals (sub-stances released by cellular stress) and exogenous small mole-cules (xenobiotics). It is noteworthy that other substances suchas alcohol, MA and opioids, may also share this mechanism[43]. These neuroimmune effects extend the current mechan-istic paradigm of drugs of abuse by identifying the immunesystem as an important component of core neural mechan-isms mediating reinforcement.

4.2. Primary behavioral effect of MA

MA is most frequently taken orally, intravenously or in smokedform. The route of administration influences the reinforcingeffects of MA with some routes producing a more immediateonset of euphoria (e.g. intravenous or inhalation). After intrave-nous injection or inhalation of MA, euphoric effects are observedwithin 5 min and last up to 8–12 h, a much longer duration ofaction than cocaine (20–30 min) [8]. The majority of the partici-pants in the clinical trials summarized in this review, used IV orsmoked MA as their preferred route of administration.

4.3. Neurobiological and toxicological effects of chronicMA use

Chronic MA use is associated with many neuroadaptations inthe CNS including hypofunction of DA activity in the reward

circuitry that is believed to mediate dysphoria and drug crav-ing [44]. Neuroadaptations also occur in other neurotransmit-ter systems including NE, 5-HT, glutamate, GABA, opioids,oxytocin, CRF as well as in the hypothalamic-pituitary-adrenal(HPA)-axis [45–47].

MA abuse also has direct neurotoxic effects on DA neuronsincluding those in the nigrostriatal pathway. The underlyingmechanism for this neurotoxicity is likely MA-induced eleva-tions in DA levels in the cytosol of neurons rather thanincreased synaptic DA levels. Because DA can produce super-oxide anion (O2

–) and other reactive oxygen species, lipidperoxidation and activation of proteases are considered tobe important mediators of DA neurotoxicity. In addition, neu-roimmune activation and release of inflammatory molecules inthe CNS (cytokines, chemokines, adhesion molecules) are likelyto be involved in the development and persistence of MAtoxicity in different brain regions [48]. Finally, MA use is asso-ciated with an increased entry of HIV and HCV into the brain[49] through MA’s immunological [50] and blood–brain barriereffects and this may contribute to the development of HIV-related neurocognitive impairment [51].

These neurotoxic effects of MA are consistent withobserved neurocognitive deficits among individuals withMUD. However, the issue of causality remains controversial.In a 2007 meta-analysis MA users (n = 471), compared tohealthy controls (n = 441), showed deficits in learning, execu-tive function, memory, and speed of information processing[52, p.20]. Importantly, these neurocognitive deficits seemedto be correlated with reduced dopamine transporter (DAT)density in the striatum and were not reversible following1 month of abstinence from MA use [53, p.2]. However, arecent critical review of neuropsychological and neuroimagingdata questioned the clinical significance of previously shownchanges in human cognition [54], while an even more recentcomprehensive review of data from animal studies, twin stu-dies, neuroimaging, cross sectional and longitudinal studiesconcluded that MA can cause cognitive decline, at least insome predisposed individuals [55]. Carefully conducted long-itudinal studies are needed to more fully characterize thenature and extent of MA-induced changes on humanneurocognition.

5. Pharmacological treatments for MUD

5.1. Dopamine agonist treatment

The primary therapeutic premise of agonist treatment for drugabuse is to replace a more addictive, unsafe drug with a lessaddictive and safer medication. Examples of established ago-nist treatment approaches include methadone and buprenor-phine for opioid use disorder and nicotine replacement fortobacco use disorder (see [56] for a critical review of theagonist treatment). Agonist treatment approaches have alsobeen examined for the treatment of MUD. Because preclinicaland clinical studies have shown that chronic exposure to MAleads to a hypo-dopaminergic state in the ventral striatum,characterized by decreases in D2 DA receptor density andhypo-responsiveness to dopamine receptor agonist challenges

308 J. BALLESTER ET AL.

[57], treatment with a D2 agonist may counteract this hypo-dopaminergic state by increasing synaptic DA activity.

To date, the agonist medications dextroamphetamine andmethylphenidate have been systematically examined in threestudies (Table 1). In an 8-week, double blind, randomized,placebo controlled clinical trial of individuals with MUD(n = 60), sustained release dextroamphetamine (60 mg/day)was no more effective than placebo in reducing MA use, asassessed by urine toxicology. However, the dextroampheta-mine group did display less craving and withdrawal symptomsthan the placebo group [15]. Similarly, in a placebo-controlled,double blind, randomized 10-week study of sustained releasemethylphenidate (54 mg) in 110 individuals with MUD, groupdifferences were not observed for self-reported days of MAuse during the last 30 days of the active phase. However, theactive group, compared with the placebo group, did reportfewer MA use days and lower cravings from baseline throughthe active phase [16]. Finally, in a recent placebo controlled,10-week clinical trial, escalating doses of methylphenidate-SRproduced less craving and MA positive urines in individualswith MUD than did placebo treatment [17].

An additional DA agonist medication currently under studyis lisdexamphetamine, a prodrug that consists of dextroam-phetamine chemically linked to the amino acid l-lysine. Onceingested, lisdexamphetamine is cleaved by enzymes withinred blood cells resulting in the release of the active dextroam-phetamine. A theoretical safety advantage of lisdexampheta-mine is its long duration of effect and reduced abuse potential[58]. Lisdexamphetamine is currently the focus of an ongoingclinical trial for MUD (NCT02034201) (Table 2).

5.2. Antipsychotics

Antipsychotics may attenuate the reinforcing effects of MA byblocking D2-type DA receptors. An added partial agonist activ-ity at D2 receptors in the ventral striatum and other brainregions could theoretically alleviate the hypo-dopaminergicstate that is associated with long-term MA use. In a rando-mized, 12-week, placebo controlled study in 90 individualswith MUD, the group treated with aripiprazole, an antipsycho-tic with D2 partial agonist activity, did not differ from theplacebo group in the number of confirmed MA positiveurine samples [21] (Table 1).

5.3. Antidepressants

The similarity of MA withdrawal symptoms and depression[59], as well as the high comorbidity between major depres-sive disorder and MUD, has led researchers to hypothesizethat antidepressants may be an effective treatment for MUD(Table 1). However, clinical trials with imipramine [13] andsertraline [14] have been negative and a recent 12 week ran-domized, double blind, placebo controlled study comparing300 mg/day of bupropion (n = 100), an inhibitor of NE and DAreuptake, to placebo (n = 104) did not find group differencesin abstinence from MA (defined as at least two negative urinesamples on weeks 11 and 12) [11, p.201]. More recently,mirtazapine, an antidepressant that enhances NE and seroto-nergic transmission by blocking both alpha2-adrenergic

receptors and 5-HT2 and 5-HT3 receptors, was examined in a12-week, double blind, randomized clinical trial in gay menwith MUD. Treatment with 30 mg mirtazapine (n = 30) ascompared to placebo (n = 30), reduced MA use measured asthe proportion of positive urine test (RR of 0.57; CI 0.35–0.93;p = .02), and also reduced sexual risk behaviors [12]. It isimportant to note that participants in these studies wereexcluded if they had a diagnosis of major depressive disorder,and, as compared to placebo, none of the antidepressantsimproved depressive symptoms as measured with establishedscales. This raises the possibility, as already stated by Newton[60], that the depressive symptoms commonly reported inearly MA withdrawal represent a distinct clinical syndrome.

5.4. GABA/glutamate modulators

Topiramate is an anticonvulsant with a complex mechanism ofaction that includes blockade of voltage-dependent sodiumchannels, increased GABA activity, antagonism of several glu-tamate receptors and inhibition of the enzyme carbonic anhy-drase. Because topiramate has demonstrated promise for thetreatment of alcohol and tobacco use disorders, it was exam-ined in a recent 13-week multicenter, randomized, doubleblind, placebo controlled study in MUD comparing 200 mg/day (n = 69) and placebo (n = 71). Although there were nogroup differences in MA weekly abstinence during weeks6–12, 30 subjects were identified as ‘responders’ by eitherhaving reduced MA use over time or by achieving abstinence.This demonstrates that topiramate may a favorable effect in asubset of individuals with MUD [19].

The pro-glutamatergic compound N-acetylcysteine (NAC) isthought to normalize extracellular glutamate levels in thenucleus accumbens by stimulating the cystine–glutamate anti-porter [61] and is clinically used for the treatment of acetami-nophen (Tylenol) overdose. NAC has been examined as atreatment for a wide range of psychiatric conditions, includingaddictions to nicotine, cocaine, cannabis and gambling [62].NAC has also been examined in the treatment of MUD in asmall randomized, placebo controlled, double blind trial of 14subjects that used a combination of NAC and naltrexone (anopioid antagonist) with negative results [22]. However, arecent study demonstrated that NAC can reduce craving inMA dependent subjects [23] and NAC may therefore be usefulas a pharmacological adjunct to behavioral interventions inpatients with MUD.

The GABA-B receptor agonist baclofen and the anticonvul-sant gabapentin, a drug with a complex mechanism of actionincluding activity at a subunit of the voltage-gated calciumchannel, have been examined in a 16-week randomized, pla-cebo controlled study of baclofen (n = 25), gabapentin(n = 26) and placebo (n = 37). Although no group differencesin primary or secondary outcomes were found, a post hocanalysis revealed a significant effect of increased medicationcompliance and reduction in MA use, especially in the baclo-fen group [20].

Finally, vigabatrin (gamma-vinyl-GABA), an antiepilepticmedication with potent GABA-enhancing properties throughits inhibition of GABA transaminase, is being studied in arandomized, double blind, placebo controlled clinical trial of

EXPERT REVIEW OF CLINICAL PHARMACOLOGY 309

180 individuals with MUD. The results are currently pending(NCT00730522; www.clinicaltrials.gov; Table 2).

5.5. Medications targeting NE and DA

In many brain regions, NE and DA transmission are closelylinked. There are neuroanatomical connections between theneurons projecting from the locus coeruleus (principal centerof NE projections in the brainstem) and DA neurons of theventral tegmental area. In addition, stimulation of NE neuronsactivates the dopaminergic system through the alpha-1 adre-nergic receptors [63]. These preclinical data suggest that themodulation of NE systems is a viable therapeutic target withthe alpha-1 adrenergic receptor antagonists prazosin and dox-azosin currently being evaluated in clinical trials for MUD(NCT01371851 and NCT01178138; www.clinicaltrials.gov;Table 2).

Other pharmacological candidates that target NE systemsinclude perindopril, an angiotensin-converting enzyme (ACE)inhibitor and candosartan, an angiotensin receptor blocker.Preclinical studies have shown an inhibitory effect of thesemedications on brain NE and DA neurotransmission althoughthe exact effects have not been fully elucidated [64]. If effec-tive, these medications could additionally reduce the elevatedcardiovascular morbidity/mortality associated with MA use(NCT01062451; www.clinicaltrials.gov; Table 2).

Finally, entacapone, a drug that increases synaptic levels ofDA and NE by inhibiting catechol-O-methyltransferase (COMT),an enzyme that degrades DA, NE and other catecholamines, iscurrently the focus of a Phase I study of MUD (Table 2).

5.6. Medications targeting the opioid system

The opioid system is thought to mediate the euphoric andrewarding effects of different substances of abuse [65]. In fact,naltrexone, a mu opioid antagonist, is an FDA approved treat-ment for alcohol use disorder. However, several different clin-ical trials on MUD have not shown a clear benefit ofnaltrexone, including the already referenced study using acombination of NAC and naltrexone [21], and a pilot studyexamining sustained release intramuscular naltrexone in MAdependent subjects carrying the A118G polymorphism of themu receptor [66]. However, in a recent laboratory study, cue-induced and subjective responses to MA were reduced inthose subjects who received naltrexone over placebo [67]. Inaddition, there are ongoing clinical trials studying the effectsof a combination of bupropion or oxazepam and naltrexone(Table 2).

An additional opioid drug with potential utility is bupre-norphine, a partial mu opioid agonist and a kappa receptorantagonist that is primarily used for maintenance therapy inindividuals with opioid use disorder. In a recent placebo con-trolled human study of 40 participants with MUD, buprenor-phine reduced cravings for MA as compared to the placebogroup [68]. However, a significant limitation of using opioidsin the treatment of MUD is the unknown risks associated withexposing patients who do not have a history of abusingopiates to a class of drugs with clear abuse liability.

6. Novel treatment approaches

6.1. Neuroimmune modulators

Cumulating evidence suggests that the pharmacologicalreduction of neuroinflammation is a potential treatment forMUD [69]. In preclinical studies, amphetamine-type stimulantsactivate microglia, an important mediator of inflammation inthe CNS, and the blockage of microglia activation prevents thereinforcing effects of MA and MA-induced neurotoxicity [70].Although limited, human studies indicate that chronic MA useis associated with microglia activation and increased biomar-kers of neuroinflammation suggesting that medications whichmodulate neuroimmune signaling, such as minocycline andibudilast, may have potential utility in the treatment of MUD.

Minocycline, an antibiotic commonly used to treat acne,has anti-inflammatory and neuroprotective effects in the CNSthat are thought to be mediated by the inhibition of microgliaactivation. Consequently, minocycline is under investigationfor the treatment of a variety of neurodegenerative and neu-ropsychiatric disorders. In a clinical study of healthy controls,5 days of minocycline (200 mg/day), compared to placebo,attenuated the subjective rewarding effects of oral dextroam-phetamine (20 mg/70 kg) and improved response inhibitionfunction as measured by the Go/No-Go task [71]. The effects ofminocycline in individuals with MUD remain to be determined.

An additional candidate neuroimmune modulator is ibudi-last, a phosphodiesterase-4 inhibitor that increases brain levelsof glial derived neurotrophic factor and reduces microglialactivation and pro-inflammatory cytokine production. In aclinical study of 7 days of 100 mg/day, ibudilast reduced theacute subjective effects of 30 mg of MA administered intrave-nously [72].

An additional feature of targeting activated glial cells is thereduction of secreted pro-inflammatory mediators that exacer-bate the neurological dysfunction caused by MA.Consequently, the pharmacological targeting of activatedmicroglia may also improve HIV-associated cognitive dysfunc-tion that is often comorbid with MUD (NCT01860807; www.clinicaltrials.gov).

6.2. Cognitive enhancement

As stated above, the chronic use of stimulants, especiallycocaine and MA, is associated with deficits in cognitive func-tioning, most notably decision-making, response inhibition,planning, working memory, and attention [73]. In clinical stu-dies of individuals undergoing treatment, these cognitive def-icits are associated with higher rates of attrition and poortreatment outcomes, possibly because these deficits interferewith the ability to engage in the treatment activities [74]. Inaddition, given that cognitive deficits may negatively affecttreatment outcomes and general functioning, regardless oftheir cause, cognitive enhancement may serve as an importanttreatment target. Consequently, pharmacotherapies that ame-liorate cognitive deficits represent a novel treatment strategyfor MUD [75] and include the use of cholinesterase inhibitors(e.g. rivastigmine or galantamine), partial nicotinic acetylcho-line receptor (nAChR) agonists (e.g. varenicline),

310 J. BALLESTER ET AL.

norepinephrine transporter (NET) inhibitors (atomoxetine), DAand NE transporter inhibitors (modafinil) and a prodrug forcholine (citicoline) [73].

Cholinesterase inhibitors have been used for the treatmentof dementia and other disorders characterized by cognitiveimpairment [38]. Rivastigmine is an inhibitor of the enzymeacetylcholinesterase that degrades acetylcholine and has beenused in a completed clinical trial that has not yet been pub-lished (NCT01073319; www.clinicaltrials.gov). Varenicline is apartial nicotinic agonist that acts on neuronal α4β2 receptorsand in a human laboratory study of 22 volunteers with MUD,pretreatment with varenicline at 2 mg was associated with areduction in the positive subjective effects of 30 mg ofsmoked MA [76]. In addition, a clinical trial has examined theefficacy of varenicline for MUD but the results have not yetbeen published (NCT01365819; www.clinicaltrials.gov).

Atomoxetine, a selective NET inhibitor used for the treat-ment of attention deficit hyperactivity disorder (ADHD), isanother promising medication targeting cognitive enhance-ment. In the prefrontal cortex, the NET is responsible for thereuptake of NE, as well as DA, into presynaptic nerve terminals[77] and the blockage of both of these actions may contributeto the cognitive-enhancing effects of atomoxetine [78,79]. Arecently completed clinical trial that examined the efficacy ofatomoxetine in individuals with MUD awaits publication(NCT01557569; www.clinicaltrials.gov).

Modafinil is a cognitive enhancer with weak stimulant-likeproperties (and hence less potential for abuse and diversion)and is approved by the FDA for the treatment of sleep apnea,narcolepsy and shift work-induced sleep disorder. It is a weakinhibitor of DA and NE transporters and has additional actionson brain GABA, glutamate and orexin [80]. In a 12-week multi-center, randomized, double blind study comparing 200 mg ofmodafinil (n = 72), 400 mg of modafinil (n = 70) and placebo(n = 68) no group differences were found in the primaryoutcome of 1 week of MA negative urine. However, thestudy was confounded by a medication adherence rate ofonly 50% as determined by urine modafinil concentrations[18]. In addition, the study did not assess cognitive perfor-mance of the study participants and it remains to be examinedif modafinil would be more effective in MA users with cogni-tive deficits, but as noted above, the interpretation of neuro-cognitive performance in the context of MA use is a complexissue requiring further study.

Finally, citicoline an intermediate in the generation of pho-phatidylcholine, a major phospholipid in biological mem-branes, also facilitates synthesis of DA and acetylcholine. Inpreclinical and clinical studies, citicoline has cognitive enhan-cing and neuroprotective properties [81] and a recently com-pleted, but yet unpublished, clinical trial has tested theefficacy of citicoline for MUD (NCT00950352).

6.3. Vaccine immunotherapies

Despite previous inconsistent results, there is a renewed inter-est in the use of immunotherapies, especially vaccines, for thetreatment of different drugs of abuse including nicotine,cocaine and MA [82]. Immunotherapies reduce the amountof drug that reaches the brain by stimulating the production

of antibodies that bind to the drug molecule after it has beensystemically absorbed during drug use. The limitations of avaccine include the prolonged time it takes to develop suffi-cient circulating antibodies, the large variation in the antibodytiter and incomplete blockage of drug effects. Furthermore,the antibodies developed are specific for a given drug mole-cule and this limits effectiveness in individuals using multipledrugs [82]. For MUD, vaccines could be most effective inpreventing relapse in individuals who use MA sporadically.While there are several ongoing MA vaccine studies, there isalso a completed clinical trial using Ch-mAb7F9, a human–mouse monoclonal antibody that binds to methylphenidate(NCT01603147; www.clinicaltrials.gov).

6.4. Oxytocin

There is cumulating evidence of a potential benefit in the useof the ‘pro-social’ hormone oxytocin for treating substance usedisorders [83]. So far, results are inconclusive with both posi-tive and negative effects in humans that may depend on thetype of substance used. Although the exact mechanismsremain elusive, some authors have proposed an inhibitoryeffect of oxytocin in the reward circuit, particularly in thenucleus accumbens and subthalamic nucleus projections[84]. A recent clinical trial will examine the potential utility ofoxytocin combined with motivational enhancement grouptherapy in HIV positive gay men with MUD (NCT02881177;www.clinicaltrials.gov).

7. Conclusions

Despite the significant advances made over the past severaldecades in the understanding of the basic neurobiology ofstimulant addiction, these advances have not been translatedinto effective pharmacological treatments for MUD. Clinicaltrials testing potential medications for MUD have largelybeen negative, and currently there are no consistently effec-tive pharmacological treatments for MUD. Novel treatmenttargets include cognitive-enhancement strategies, the modu-lation of the neuroimmune system and immunotherapythrough vaccine development. These and other promisingtreatment approaches need to be tested in well designedand adequately powered clinical trials while the results ofrecent studies with novel therapeutic targets awaitpublication.

8. Expert commentary

Similar to MUD, there are no effective pharmacological treat-ments for addiction to cocaine, a similarly acting stimulant forwhich a much larger number of clinical trials using variousmedications has been conducted. This failure in progress fordevelopment of pharmacological treatment for MUD could beinfluenced by multiple factors including small sample sizes inthe majority of studies compounded by high dropout rates, inthe range of 40–50 %. Therefore, the majority of clinical phar-macological trials for MUD are simply underpowered. In addi-tion, there is also an ongoing debate about which clinicallysignificant outcome measures should be used in clinical trials

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of stimulant use disorders. Future work should address thesemethodological limitations.

As noted earlier, individuals with addiction, including thosewith MUD, have many comorbid disorders including otheraddictions, anxiety, psychosis and mood disorders. These dis-orders have overlapping symptom clusters across differentdiagnostic categories and therefore, new treatmentapproaches that use trans-diagnostic treatment targets, ratherthan trying to develop specific treatments for individual addic-tions and other psychiatric disorders, may be constructive.Consistent with the Research Domain Criteria (RDoC) initiativeof the National Institute of Mental Health (NIMH), using suchan approach is responsive to what some have called a ‘ther-apeutic stagnation’ for mental health disorders. The proposedRDoC approach, by identifying trans-diagnostic treatment tar-gets, may be especially fruitful in developing pharmacothera-pies for highly comorbid conditions like stimulant addictionwhere neuroimmune mechanisms, especially microglia activa-tion and cognitive deficits, are relevant targets across a rangeof psychiatric disorders. Although not novel for other addic-tions, immunotherapies for MUD have already demonstratedsome promising findings.

Finally, pharmacogenetics is another area of research that mayenhance the benefits from pharmacotherapies for SUDs. Theability to predict treatment response and adverse effects basedupon genetic markers can lead to an optimal treatment match-ing. While promising, the effect of pharmacogenetic testing ontreatment outcomes in clinical settings requires further study.

9. Five-year view

An important issue that has not yet been addressed is thedevelopment of a consensus on the main outcome measuresto be used across clinical trials for MUD. Currently, clinical trialsuse a wide range of outcome measures focusing on MA useduring the clinical trial. However, the clinical significance ofthese measurements is not always clear. The standard out-comes that are widely used for clinical trials in tobacco andalcohol use disorder are noteworthy predicates to consider inthis regard. In addition, given the historically low retentionrates in MA studies, sample sizes need to be increased toensure that future clinical trials have adequate power to testthe efficacy of promising treatments. Conducting multisitestudies can help with addressing this sample size issue, whileinterventions like contingency management are effective inimproving retention. With the implementation of improvedclinical trial methodology, the field will be better positionedto effectively test the potential for novel treatments of MUD.

Key issues

● On a global basis, methamphetamine (MA) and relatedstimulants continue to be the second most widely abuseddrug class after cannabis. Currently available treatments formethamphetamine use disorder (MUD) are primarily beha-vioral and have limited efficacy.

● Despite considerable effort, no medications have beenapproved for the treatment of MUD. Numerous clinical trialshave been conducted utilizing medications that act on a

variety of different targets including DA agonist treatments(dextroamphetamine, methylphenidate), antipsychotics (ari-piprazole), antidepressants (imipramine, sertraline, mirtaza-pine, bupropion), GABA/glutamate modulators (topiramate,N-acetylcysteine, baclofen and gabapentin). Other pharmaco-logical systems are currently under study and include medica-tions targeting NE and DA (prazosin, doxazosin, candosartan,entacapone), and the opioid system (naltrexone,buprenorphine).

● Novel and exciting approaches for the treatment of MUDinclude neuroimmune modulators (minocycline, ibudilast),cognitive enhancers (rivastigmine, galantamine, varenicline,atomoxetine, modafinil, citicoline), vaccines, and oxytocin.

● The future of the field will likely depend on overcomingmethodological limitations (high drop-out rates, small sam-ples, agreement on outcome measures), and might benefitfrom the development of trans-diagnostic criteria.

Funding

This research was supported by the Veterans Administration Mental IllnessResearch, Education and Clinical Center (MIRECC).

Declaration of interest

The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

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