Medication Treatment Options for Amphetamine-Type Stimulant Users / Leejenn Health Consultants; (Nicole Lee & Linda Jenner)

Medication treatment stimulant users amphetamine-type options for 29 ANCD research paper 29

Medication paper ANCD research treatment options for amphetamine-type stimulant users

LeeJenn Health Consultants

A discussion paper prepared for the Australian National Council on Drugs, November 2013 © Australian National Council on Drugs 2014 This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without the written permission of the publisher.

Published by the Australian National Council on Drugs PO Box 205, Civic Square ACT 2608 Telephone: 02 6166 9600 Fax: 02 6162 2611 Email: [email protected] Website: www.ancd.org.au

National Library of Australia Cataloguing-in-Publication entry Medication treatment options for amphetamine-type stimulant users / LeeJenn Health Consultants; (Nicole Lee & Linda Jenner). ISBN: 9781877018329 (ebook) ANCD research paper; 29. Includes bibliographical references. Amphetamine abuse — Treatment Amphetamines Stimulants Therapeutics Lee, Nicole Jenner, Linda LeeJenn Health Consultants Australian National Council on Drugs 616.864061

Editor: Julie Stokes Design: Inkwire, Canberra

Acknowledgement: This work has been supported by funding from the Australian Government Department of Health and Ageing. The opinions expressed in this publication are those of the authors and are not necessarily those of the ANCD or the Australian Government.

iii Research Council, based at the University of Sydney. She recently completed a National Institute Institute National a completed recently She Sydney. of University the at based Substance Council, Integrated Research UCLA at Fellowship INVEST Network Trials Clinical (NIDA) Abuse Drug on in buprenorphine examining trial clinical multi-site national a on focusing Programs Abuse worked as she a pharmacist for cocaine dependence. Previously of the naltrexone presence Alcohol and Drug Centre. Point at Turning Fellow and Senior Research . website: LeeJenn Health Consultants clinical guidelines, delivered training, and developed and evaluated treatment programs. treatment and evaluated and developed training, delivered clinical guidelines, Medical and Health National the with Fellow Research Career Early an is Nielsen Suzanne Dr Linda Jenner is a registered nurse and holds a Masters in Applied Science (Research). She has has She (Research). Science Applied in Masters a holds and nurse registered a is Jenner Linda worked as a clinician,educator researcher, and consultant in the alcohol and other drugs Senior a was she Consultants, Health LeeJenn to Prior 1978. since fields health mental and Research Fellow in Clinical Research at Turning AlcoholPoint and Drug Centre and wrote Drugs and the Alcohol and other Drugs Council of Australia, and was the Queensland, Victorian Victorian Queensland, the was and Australia, of Council Drugs other and Alcohol the and Drugs and Behaviour Therapy. for Cognitive Association of the Australian and National President Nicole Lee is a practising psychologist, Associate Professor at the National Centre for Education Education for Centre National the at Professor Associate psychologist, practising a is Lee Nicole Curtin at appointments adjunct holds and University, Flinders at Addiction on Training and Consultants. Health LeeJenn of co-director is she Jenner, Linda With universities. Monash and other and Alcohol on Society Professional Australasian the of boards the on served has She About the authors Acknowledgements This project could not have been completed without substantial assistance. LeeJenn Health Consultants are very grateful to the Australian National Council on Drugs for their support of this work. We would like to extend a special thank you to Michele Hawkins for her boundless patience and for the special treats that kept the project moving along so well. We also thank our colleagues Jacqui Cameron, for her tireless assistance with the searches and retrieval of papers, and Jason White for conducting the final review. We also acknowledge with gratitude the generous contributions of time and expert opinions offered by the Reference Group, including assisting with the development of search criteria, advising on the search strategy, and reviewing several iterations of the discussion paper. Members of the Reference Group were: • Robert Ali • Amanda Baker • Jon Currie iv • Adrian Dunlop • Margaret Hamilton • Nick Lintzeris • Steven Shoptaw • Jason White v x 1 1 1 2 3 4 4 8 9

iv ix ix iii

vii vii 11 11 10 10 12 12 12

viii xiii xiii

......

dependence

......

. pharmacotherapies Functional agonist . . Dopamine antagonists ...... Withdrawal from amphetamines from Withdrawal amphetamine dependence for Treatment . . .amphetamine with problems health mental co-occurring of Treatment ...... craving to reduce Pharmacotherapies . . Other medicines ...... Treatment of other amphetamine-type stimulant dependence of other amphetamine-type Treatment Background Methods Main findings Screening and extraction Screening Analysis Amphetamine-type stimulant use in Australia in Amphetamine-type stimulant use of amphetamine-type stimulants of action Primary mechanisms of amphetamine-type stimulants and harms consequences Effects, stimulant users for amphetamine-type treatment Psychosocial in amphetamine-type stimulant treatment Medicines and their potential uses Methods Search strategy Search criteria and exclusion Inclusion Acknowledgements summary Executive

About the authors ...... Contents Introduction Purpose of this review Purpose of this Detailed findings ...... 14 Amphetamine and methamphetamine ...... 14 Withdrawal from amphetamines ...... 14 Treatment for amphetamine dependence ...... 18 Treatment for co-occurring mental health problems among amphetamine-type stimulant users ...... 28 MDMA ...... 30 Other amphetamine-type stimulants ...... 31

Conclusions ...... 32

References ...... 34 Studies included in the systematic review ...... 42

Appendix: Summary tables ...... 48 Amphetamine withdrawal ...... 48 vi Treatment for amphetamine dependence ...... 58 Dexamphetamine and other psychostimulants ...... 58 Modafinil ...... 68 Bupropion ...... 74 Naltrexone ...... 80 Antipsychotics ...... 82 Anticonvulsants ...... 86 Antidepressants ...... 90 Flumazenil and gabapentin combination ...... 94 Medicines not otherwise specified ...... 98 Comorbidity ...... 102 MDMA ...... 110 Other amphetamine-type stimulants ...... 110

Tables and figures Table 1: Overview of studies reviewed for the treatment of amphetamine-type stimulant dependence ...... 26 Figure 1: Search, screening and review procedure ...... 13 Executive summary vii

specifically for ATS treatment. for specifically of ATS dependence or withdrawal, leaving an important gap in evidence-based treatment for options health and workers a of their is range about There broad views clients. the use and generally, more sector treatment drug other and alcohol the within pharmacotherapy of subsequent relapse rates are high, prompting strong interest in pharmacological treatments. treatments. pharmacological in interest strong prompting high, are rates relapse subsequent sufficient demonstrated have medications no far so efforts, research considerable with Even treatment the for internationally or Australia in approval widespread warrant to effectiveness In recent years, considerable attention has been focused on developing effective psychosocial psychosocial effective developing on focused been has attention considerable years, recent In interventions for ATS andusers psychological interventions are currently the treatment of choice. Yet, despite the effectiveness of psychosocial approaches, treatment attrition and of ATS use are severe and typically when abstinence is the treatment goal. Clinicians and to group this for pharmacotherapies effective into research more for called have researchers into treatment. users ATS more attract and options treatment broaden of dependent users entering treatment. Many users attempt to withdraw from ATS without ATS from withdraw to attempt users Many treatment. entering users dependent of specialist supervision, and the consequences use ofthe other when illicit only drugs to treatment self-manage formal the seek symptoms to of tend users ATS common. is withdrawal concentration concentration and impaired decision making, memory, insomnia, mood irritability, swings, and lack of motivation. activities, in pleasurable loss of interest cent per 20 than less with treatment, in retain and attract to difficult notoriously are users ATS users users up to one year following abstinence. Serotonin is also thought to be depleted after chronic exposure, particularly in users of 3,4-methylenedioxymethamphetamine (MDMA), with often experience problems As users a ATS commonly consequence, known as ecstasy. Neurotoxicity is associated with chronic and long-term exposure to ATS, with imaging studies studies imaging with ATS, to exposure long-term and chronic with associated is Neurotoxicity methamphetamine of brains the in reductions transporter dopamine significant demonstrating Regular long-term use of ATS can result in dependence, especially in those who use by injection or can On smoking. dependent experience cessation, users a of range withdrawal while motivation, of lack and depression dysphoria, irritability, insomnia, as such symptoms a common feature. also is to use craving strong effects of these actions manifest differently among people who use ATS during intoxication intoxication during ATS use who people among differently manifest actions these of effects irrit agitation, mood, low (e.g. withdrawal and confidence) energy, increased euphoria, (e.g. endeavour. complex a agents pharmaceutical effective of identification the making ability), Amphetamines and their analogues are complex drugs that have multiple mechanisms of action in the brain, including stimulating release of monoamines, blocking re-uptake of adrenergic and dopaminergic neurotransmitters, and inhibiting monoamine oxidase. The Australia has one of the highest rates of amphetamine-type stimulant (ATS) use in the world. world. the in use (ATS) stimulant amphetamine-type of rates highest the of one has Australia and year, past the in ATS used have years 14 of age the over people of cent per 2.5 Around users. than 72 000 may be dependent estimates suggest more Background Executive summary Executive viii Medication treatment options for amphetamine-type stimulant users and case studies). They differ from a general review in that the search method and the the and method search the that in review general a from differ They studies). case and qualitative (including study of type any include can and vehicle primary their as method pretation of findings, was undertaken. Systematic reviews use a thorough, systematic search A systematic review method, coupled with a modified meta-narrative approach to the inter Methods identification ofareas forconcentration offuture research effortsin Australia. related to the next steps, including the development and updatingdiscussion of guide clinical to guidelines,help to and designed also is review The potential. show medicines which including conditions, related and dependence ATS of treatment the in medicines for role This review of the evidence for pharmacotherapies for ATS treatment articulates the potential in-depth meta-narrative analysis ofidentifiedstudieswasundertaken. an review,the and in considered was significance clinical and statistical Both ATS. on ent conversely whether there are medicines that are unsafe to use with people who are depend- and plan, comprehensivetreatment a of part forming promisein show that medicines are This review was designed to examine, in greater detail than previous reviews, whether there Purpose ofthisreview and studiesofpharmacotherapy responses toacutetoxicity. contexts (e.g. used healthy volunteers or used dependent volunteers in a laboratory setting), or non-treatmentparticipants primarily included that participants,studies non-dependent published prior to 1997, qualitative studies, general reviews, studies that included primarily Council levels of evidence). Excluded were animal studies, non-English manuscripts, studies and at least Level IV methodology (according to the National Health and Medical Research 1997 and 2013 (last 15 years), manuscripts in English or with available English translation, Included papers were human studies, studies of adult participants, articles published between of specific papers also identified someadditionalstudies. Systematic Reviews. The search period was January 1997 to January 2013. Hand-searching of Database Cochrane the and PsycINFO,Embase MEDLINE, weresearched databases The ‘why’, ‘how’,‘forwhom’and‘inwhatcircumstances’. to ‘what’ beyond look to and data the in differences and similarities examine to designed the weight of the evidence is for or against the use of a medicine), meta-narrative review is is,whether (that ‘all-or-nothing’ as evidence the interpreting and presenting than Rather help researchers interpret the literature when methods, measures and outcomes vary widely. evaluation of the articles are explicit and replicable. A newer form of review has emerged to - Executive summary ix - mg of amineptine demonstrated effectiveness in some studies, there is some some is there studies, some in effectiveness demonstrated amineptine of mg

mg of dexamphetamine demonstrated effectiveness in reducing withdrawal symp withdrawal reducing in effectiveness demonstrated dexamphetamine of mg

mg of modafinil demonstrated effectiveness, when tolerated by patients, in reducing reducing in patients, by tolerated when effectiveness, demonstrated modafinil of mg

mg of mirtazapine demonstrated effectiveness in reducing withdrawal symptoms in

toms in some participants over a 2–8 week period in some participants over toms 300 although in Australia. unavailable currently potential and it is question about its abuse some participants over a 14-day period; lower doses did not produce convincing effects convincing produce not did doses lower period; 14-day a over participants some 400 day period; lower a doses in 7–10 did some symptoms not participants withdrawal over convincing effects produce 60–110 60 • • • • Main findings Most of the studies reviewed had small sample sizes and the outcomes were variable. In addition, ATS users in treatment drop out at high rates effectiveness and the confirm thereto warranted is is a highresearch Further relapsewithdrawal. ATS after rate and during of these medicines. small small number of studies and the lack of strong evidence either for or against the routine required is research further withdrawal, ATS for pharmacotherapy as medicines these of use of clinical guidelines. to inform the development There were no serious adverse events reported in the 12 studies reviewed, but given the dexamphetamine may have a potential role in the range of symptom-management strategies strategies symptom-management of range the in role potential a have may dexamphetamine clinical Future investigation. further merit and withdrawal, methamphetamine for available and used, be could medicines these which under circumstances the detail should guidelines use. their safe that would ensure strategies for whom, and the medical monitoring In summary: in Australia. Modafinilis thought to act on the dopamine while transporter, mirtazapine is known to enhance noradrenergic and serotonergic transmission. Dexamphetamine and of monoamines at the synaptic cleft. levels increasing amineptine both work by The although evidence limited, from this suggests review, that modafinil, mirtazapine and Of the four medicines that have been studied for withdrawal from amphetamines, modafinil, modafinil, amphetamines, from withdrawal for studied been have that medicines four the Of and withdrawal ATS during benefits some offer to appear dexamphetamine and mirtazapine may also assist with relapse prevention. The fourth medicine, amineptine, is not available There was no evidence found for the use of benzodiazepines though or othereven medicineswithdrawal, in for the users ATS among agitation or disturbance sleep of management in clinical guidelines. commonly recommended these medicines are withdrawal were reviewed. The evidence was inconclusive but, despite small sample sizes, compared effects non-significant showed medicines Where found. were results positive some improved. participants in both groups to placebo, in general Withdrawal from amphetamines from Withdrawal Twelve separate studies that reported the effects of medicines on any symptom of ATS x Medication treatment options for amphetamine-type stimulant users and showed somebenefitinthestudies reviewed: The following medicines were reported to be reasonably well tolerated by research participants confidence. with interpreted be to AustraliausersATSand in of population broader the generalisedto to date are smaller-scale feasibility studies. Larger RCTs are required to enable results to be preventing relapse or among use dependent methamphetamine ATS users. reducing All of in the studies conducted effectiveness of evidence consistent demonstrated medicine No all RCTs. The evidenceis sparse fortheremainder. trolled trials (RCTs); followed by modafinil (five) including three RCTs; and bupropion (four), been the subject of the greatest number of studies (seven), including four randomised con - Dexamphetaminehas writing. of time the at studies relativelyfew of subject the been has Thirty-nine studies were identified, examining 18 potential pharmacotherapies, though each Treatment foramphetaminedependence 8–12 weeks, so the effectiveness and safety of these medicines for long-termpants under local conditionsuse of ATS areuse. Most of unknown.the studies reviewed were conducted over evidence. These medicines require further research with large numbers of Australian partici- be recommended for routine treatment of methamphetamine dependence due to insufficient Although these medicines appear to have been beneficial for some participants, they cannot • • • • • daily from week3onwards (optimaltime fordailydosingwasnotspecified). starting dose of 18 of dose starting a was effectivedose improvemost may reduceuse.The Methylphenidate retentionand dose was50 mgperday(optimaltimefordailydosingunspecified). effective most The craving. reduce and treatment in improveretention may Naltrexone (150 mg morningand150evening). 300 to ing month) and men. The most effective dose was a starting dose per of use 150 days (<18 users ATS ‘lighter’ by use ATS reducing in effective was Bupropion morning tolimitsleep disturbance. 400 was dose effective most The medicine-compliant. were who those among use ATS reducing in placebo to superior be to found was Modafinil to limitsleep disturbance. treatmentretention.effective100 most was The dose increase and dependence ATS of severity the reduce to found was Dexamphetamine mg per day after three days taken either in the morning or in divided doses divided in or morning the in either taken daysthree after day per mg mg daily increasing to 36 to increasing daily mg mg daily in the second week, and 54 and week, second the in daily mg mg per day taken in the morning the in taken day per mg

mg per day taken in the the in taken day per mg

mg per day increas mg - Executive summary xi - Prometa™ protocol of combination flumazenil and gabapentin (unacceptable adverse effect profile). ondansetron (limited evidence of benefit) (limited evidence of ondansetron amlodipine (limited evidence of benefit) effect profile) (unacceptable adverse aripiprazole effect profile) vigabatrin (unacceptable adverse effect profile) (unacceptable adverse sertraline baclofen (limited evidence of benefit) gabapentin (limited evidence of benefit) mirtazapine fluoxetine topiramate risperidone varenicline. • • • • • • • • • • • • • the evidence has been gained from international studies, research is needed to examine the examine to needed is research studies, international from gained been has evidence the Australia. in adults ATS-dependent treating for promise show that medicines of effectiveness sample sample sizes while poor participant retention and low adherence to prescribed pharmaco in ATS use to tend Australians results. high-quality gaining to barriers common were therapy of most as and, injecting) of rates high (e.g. countries other in users from differ that patterns patients in pharmacotherapy treatment and to improve medication adherence may be useful. be may adherence medication improve to and treatment pharmacotherapy in patients The studies showed variable outcomes and some results were conflicting. Many hadsmall Overall, many studies were conducted on small numbers of participants and there were high high were there and participants of numbers small on conducted were studies many Overall, retain to ways examines that research Future adherence. medication low and rates drop-out recommended for use or as a high priority for further study: or as a high for use not recommended They are Other medicines showed either limited or no benefit, or an unacceptable adverse effect profile. profile. effect adverse unacceptable an or benefit, no or limited either showed medicines Other psychosis, epilepsy and smoking cessation: epilepsy and smoking psychosis, required. required. Each utilises a different pharmacological approach, including noradrenergic and serotonergic agents, dopamine antagonists and a nicotinic receptor partial agonist. These potential medicines are all used currently for a range of indications, such as depression, A number of other for medicines the promise showed of treatment amphetamine - depend ence but as the number of studies is too small to draw additional conclusions, research is xii Medication treatment options for amphetamine-type stimulant users may have masked theeffectiveness ofthemedicines. varied between studies, psychosocial interventions for both the treatment and placebo groups in conjunction with pharmacotherapy. Although rates of attendance at counselling sessions Nearly all of the studies reviewed utilised psychosocial interventions, some quite intensively, Role ofpsychosocial interventions medicines asprescribed mayalso improve outcomes. is, a program of planned incentives for treatment goals met) to increase adherence to taking time they remain in treatment. The use of strategies such as contingency management (that of length increasethe can medicines that suggests evidence the treatment,and enter who psychosocialwith ATStherapiestherapiesconjunction of increase usersin number will the pharmaco providing that argue clinicians Some success. treatment for necessary also is rates were very high, suggesting that helping clients maintain their motivation for treatment of adherence is important for ensuring effectiveness of treatment. In some studies, attrition found a correlation between medication adherence and better outcomes, so carefulstudies,the of most In adherence prescribedas medicines taking to low.was studies Many monitoring Role ofadherence toprescribed medicines Other considerations inthetreatment ofamphetamineuse results foranAustralian clinicalsetting. States rarely included injecting methamphetamine users. Care is needed in translating these United the from studies 2012)Burns, and & (Stafford ATS use cent per 70 approximately injection, by drugs use who Australians differ.Among country each in systems treatment important consideration for Australia because the nature of methamphetamine an useis and This the America. of States United the in undertaken were studies the of majority The Cultural differences CBT, andhave notedthatthequalityofresearch is relatively poor(e.g. Ost,2008). ACT have found it to be effective with other disorders, but no more effective than traditional users on their own or in conjunction with medicines. Systematic reviews that have examined ATS with effective are interventions these whether on guidance little providingliterature, ance and commitment therapy (ACT), but these studies remain unpublished in the peer review There is some emerging work on ‘third wave’ CBT interventions for ATS users, such as accept created a ceiling effect in some studies that is unlikely to be replicated in the clinical setting. therapeutically beneficial (Kypri, Langley, Saunders & Cashell-Smith, 2007), which may have isassessmentitself that protocols.suggest their to of Thereisevidence procedurespart as assessment intensive employed studies the of many that is factor complicating Another treatment settings, have beenshown tobeeffective among methamphetamineusers. Australian in widely offered is which intervention, therapy(CBT) behaviour cognitive brief extensively in the United States of America, andusedis which 1995), the al., et (RawsonBaker Model Matrix the et as interventions, such Psychosocial al. (Baker et al., 2005) four-session - Executive summary xiii - - therapies is likely to be more productive if focused on treating methamphetamine dependence. methamphetamine treating on focused if productive more be to likely is therapies Given the very small numbers of dependent users of other ATS, research into pharmaco for the effectiveness of pharmacotherapy for MDMA treatment and, with the exceptions of exceptions the with and, treatment MDMA for pharmacotherapy of effectiveness the for psychosocial symptoms, health mental co-occurring or withdrawal from relief symptomatic of choice for MDMA users. the treatment remains intervention treating for medicines of role the examined that identified was design single-case one Only dependence other than methamphetamine and MDMA. ATS identified for this review and both were single-case designs. Overall, there was little evidence evidence little was there Overall, designs. single-case were both and review this for identified Treatment of other amphetamine-type stimulant dependence of other amphetamine-type stimulant Treatment Other than methamphetamine, very few other ATS result in significantly problematicuse. MDMA for rare is it and toxicity acute involve MDMA with associated problems the of Most heavy use. to be associated with chronic were dependence MDMA treating for medicines of role the examined that studies two Only users users if used within existing guidelines for the general population of people with mental required. is research evidence, additional the lack of specific but, given health disorders; health problems who use ATS. A range of medicines, including antipsychotics, dexampheta antipsychotics, including medicines, of range A ATS. use who problems health mine, modafinil and citicoline, were found to besafe in the studiesreviewed and may be effective for treatment of co-occurring mental health among problems methamphetamine The dominance of case studies, coupled with a lack of standard measures, makes it difficult to difficult it makes measures, standard of lack a with coupled studies, case of dominance The mental with people for medicines these of effectiveness the about conclusions specific draw Treatment of co-occurring mental health problems with of co-occurring mental health problems Treatment amphetamine dependence Gender differences in outcomes were rarely reported in the studies reviewed. However, Elkashef Elkashef However, reviewed. studies the in reported rarely were outcomes in differences Gender et al. (2008) reported that bupropion was associated with reduced methamphetamine use in men but not women. free week than heavier users during treatment may there with that suggest bupropionanalyses post-hoc comparedoverall, benefit with show not placebo. did bupropion Although use in the last 30 days). of (e.g. <18 days users be some benefit for less frequent modafinil taking participants HIV-positive for outcomes poorer found (2009) al. et Shearer outcomes for methamphetamine-dependent participants with comorbid opioid and poorer methamphetamine dependence only. to those with dependence compared methamphetamine at baseline, bupropion treatment increased weekly periods of abstinence abstinence of periods weekly increased treatment bupropion baseline, at methamphetamine (56%) compared to placebo (40%), and less frequent users also showed a greater rate of methamphetamine- a have to in decrease urine methamphetamine quantitative than placebo. Shoptaw et likely al. (2008) also more times three nearly were users frequent less that found conditions, might benefit subgroups of amphetamine users. of amphetamine benefit subgroups might conditions, of use ‘lighter’ had who participants of subgroup the for that, showed (2008) al. et Elkashef Subgroups of amphetamine users of amphetamine Subgroups Very little evidence is available about which particular medicines prescribed, under what 1 Introduction (dopamine, noradrenaline noradrenaline (dopamine, 1 000) had used methamphetamine methamphetamine used had 000)

000 people aged 14 years and over had used ecstasy (3,4-methylene ecstasy used had over and years 14 aged people 000

Monoamines are a particular class of neurotransmitter that have a single amine group in their in a single amine group that have a particular class of neurotransmitter Monoamines are molecular structure.

1 - regula pressure blood and temperature movement, physical perception, thinking, sleeping, tion, pain control and sexual behaviour. Noradrenaline is primarily involved in the ‘fight or itflight’response: stimulates the system to central nervous increase heart function and attention, learning and memory. concentration, blood circulation, MDMA primarily exerts whereas Methamphetamine primarily affects the dopamine system, (Majumder & White, 2012). system its action on the serotonergic - develop the influence to thought is which reward, for pathway primary the is It behaviour. & Wang, Fowler 2002). ment and maintenance of (Volkow, drug dependence and cravings appetite, mood, of control including activities important of variety a in involved is Serotonin cleft. Stimulant effects are also achieved by increasing release of monoamines, or inhibiting or monoamines, of release increasing by achieved also are effects Stimulant cleft. 2008). (Rose & Grant, down monoamines enzymes that break The dopamine system is involved in movement, attention and memory, and purposeful mines and their structural analogues increase levels of monoamines of levels increase analogues structural their and mines and serotonin) through a number synaptic of includingthe mechanisms, inhibiting at re-uptake through monoamines of concentrations higher in resulting systems, transporter various Amphetamines and their analogues are complex drugs that have multiple mechanisms of and with- during intoxication manifest differently the effects of which action in the brain, through primarily systems, neurotransmitter by mediated are ATS of effects initial The drawal. Ampheta- systems. noradrenergic and serotonin the through also but system dopamine the Primary mechanisms of action of amphetamine-type stimulants amphetamine-type of action of mechanisms Primary & Payne, 2012), compared to about 11 per cent of detainees who tested positive for heroin heroin for positive tested who detainees of cent per 11 about to compared 2012), Payne, & are therapies pharmacological for which effective 2012) Crime Commission, (Australian use widely available. A 2011 report showed an increase in A methamphetamine 2011 use among police detainees, with (Sweeney 2009 in cent per 13 and 2010 in cent per 16 from up positive, testing cent per 21 2010, 3 per cent or 550 or cent per 3 2010, dioxymethamphetamine, MDMA) in with the the year, previous highest use among people 2011). of Health and Welfare, Institute (Australian (10%) 29 years aged between 20 and Amphetamine-type stimulants (ATS) include methamphetamine, MDMA and a range of other other of range a and MDMA methamphetamine, include (ATS) stimulants 2010, Amphetamine-type In world. the in use ATS of rates highest the of one has Australia analogues. synthesised 400 (about over and years 14 aged people of cent per 2.5 In year. previous the in use reporting olds year 20–29 of cent per 6.8 with year, past the in Amphetamine-type stimulant use in Australia stimulant use Amphetamine-type Introduction 2 Medication treatment options for amphetamine-type stimulant users stimulants Effects, consequences andharms ofamphetamine-type or ingested methamphetamine were dependent (McKetin, Ross, Kelly & Baker, 2008). On On 2008). Baker, & Kelly Ross, (McKetin, dependent were methamphetamine ingested or among injectors (62%) and smokers (53%), while 25 per cent of those who usually snorted phetamine users in Sydney, McKetin and colleagues found the highest rates of dependence Regular long-term use of ATS can result in dependence. Among a sample of regular metham symptoms (McKetin, McLaren, Lubman&Hides, 2006). psychotic and paranoia depression, experience can time some at users long-term many Adverse psychological effects, such as anxiety, irritability and insomnia, can also occur, while heart attackandseizures. chest pain, tremors, dangerously high body temperature, muscle spasm, brain haemorrhage, elevated blood pressure, rapid heartbeat and palpitations. Acute toxic effects of ATS include Short-term physiological consequences can include restlessness and agitation, teeth grinding, can last for around 8–10 hours due to the long half-life of ATS (Cruickshank & Dyer, 2009). inhibitions and heightened sexual arousal (Halkitis, Fischgrund & Parsons, 2005), all of which ness and reduce appetite. Users also report increased self-esteem and sociability, lowering of The rapid release of neurotransmitters caused by ATS acts to boost energy, promote wakeful (Salo etal.,2009). many months to recover, during which time impulsive behaviour may be difficult to control requireexecutivefunctioning and focus attentional that suggesting more, or yearabstinent one for been had who those to compared when attention) her or his direct to ability have been found to perform significantly worse on the Stroop Test (a measure of a person’s usersmethamphetamine abstinent Newly motivation. of lack and activities,pleasurable in and memory, impaired decision making, irritability, insomnia, mood swings, loss of interest concentration with problems experience often usersATS consequence, a As 2004). Dean, 2006; al., et (Barr usersMDMA in of chronicexposure,particularly after depleted similarly users up to one year following abstinence (Volkow et al., 2001). Serotonin is thought to be demonstrating significant dopamine transporter reductions in the brains of methamphetamine Neurotoxicity is associated with chronic and long-term exposure to ATS, with imaging studies to use also commonlyfeature inATS withdrawal states(Jenner&Saunders, 2004). as insomnia, irritability, dysphoria, depression and lack of motivation, while strong cravings cessation of ATS use, dependent users can experience a range of withdrawal symptoms, such - - 3 Introduction 000 000 closed treatment episodes for which amphetamine was was amphetamine which for episodes treatment closed 000

000 Australians 000 who more Australians used than methamphetamine 72 regularly, to broaden treatment options and attract and retain more ATS users in treatment (Kenny & Lee, 2009). Pennay et al., 2011; ment of people dependent on opioids (Mattick, Breen, Kimber & Davoli, 2009), clinicians users ATS for pharmacotherapies effective into research more for called have researchers and tions are tailored specifically for stimulant users, only about 40 per cent complete treatment treatment complete cent per 40 about only users, stimulant for specifically tailored are tions et al., 2004). (Rawson As pharmacotherapies such as methadone have been shown to increase retention in - treat Despite the effectiveness of psychosocial approaches, treatment attrition and subsequent high, are particularly rates dependence relapse among and people longer with severe more - interven psychosocial when Even 2005). Anglin, & Greenwell (Brecht, use ATS of duration third of treatment completers, and detoxification, which was found to have similar outcomes outcomes similar have to found was which detoxification, and completers, treatment of third step first a as only used be therefore should and 2012) al., et (McKetin all at treatment no to program. treatment in a structured among ATS users (Baker et al., 2005). (Baker et al., users among ATS was which rehabilitation, residential include users ATS to available options treatment Other found to be associated with in reduction short-term methamphetamine in use about one- both demonstrated effectiveness in assisting ATS users to attain abstinence (Lee & Rawson, Rawson, & (Lee abstinence attain to users ATS assisting in effectiveness demonstrated both mental co-occurring sessions addressing of benefit the have four also interventions that Psychological 2008). found example, for study, Australian One users. ATS among problems health depression of severity the reduced significantly also and abstinence of rates increased CBT of for this group in recent years and structured psychological interventions are currently the reinforcers immediate uses that approach an management, Contingency choice. of treatment have (CBT) therapy behaviour cognitive and behaviour, drug-free reward to vouchers as such Many users attempt to withdraw from ATS without specialist supervision, and self-medication self-medication and supervision, specialist without ATS from withdraw to attempt users Many Harney, (Kenny, common is withdrawal of symptoms the manage to drugs) illicit other (using consequences the when only treatment formal seek to tend users ATS 2011). Pennay, & Lee 2004) and typically Gowing, when Lee abstinence & is Proudfoot, (Baker, severe are of use et al., 2011). the ultimate goal (Kenny interventions psychosocial effective developing on focused been has attention Considerable period there were fewer than 15 than fewer were there period 2013). of Health and Welfare, Institute concern (Australian the primary drug of For For more than a decade, clinical have researchers highlighted the reluctance of ATS users to enter treatment (Vincent et al., 1999). In 2005, for estimated example, that researchers among the 100 same the in yet 2005), Hickman, & Hall Kelly, McLaren, (McKetin, dependent be to likely were Psychosocial treatment for amphetamine-type stimulant users stimulant amphetamine-type for treatment Psychosocial 4 Medication treatment options for amphetamine-type stimulant users stimulant treatment Medicines andtheirpotentialuses inamphetamine-type limiting itsrewarding effects. thereby concurrently, used is it if drug target the of effect the reduce medicines agonist drug and triggering a similar but moderated or less target intense the effect. as In system some nervous cases, central functional the in receptors same the to binding by work They Functional agonist pharmacotherapies possess properties similar to the target drug of concern. Functional agonist pharmacotherapies mine dependence,thoughreports from recent animalstudiesshow promise. been investigated. Unike cocaine, there has been no human trial of a vaccine for ampheta- targetthat those specific symptoms with associated ATS depression, as such use, have also improveand to cognition unclear.known still isMedicines action mechanismexactof the neurotransmitter systems, but also the serotonergic and gabaergicneurotransmitterdopaminergic systems, key primarily of systems.modulation through effects their For some medicines vulnerabilities and common symptoms of withdrawal and dependence. The medicines achieve psychiatriccraving, rewardand pathwaysincluding dependence, mechanismsATS lying of The medicines that have been trialled in the reviewed studies target a wide range of under- & Galloway, 2001). trigger relapse (Brensilver, Heinzerling, Swanson & Shoptaw, 2012; Hartz, Frederick-Osborne may that cravingwithdrawal-related including symptoms,withdrawal physical minimising and frequency); and (quantity use ATS illicit reducing ATS; illict of effects adversesevere that medicine a stimulates the central nervous systemof in ways that may be acceptable to users but lack the dose legal and known stable, a providing neurochemistry; malising nor- include ATStreatmentdependence of the in agonistrolesmedicines of potential The therapies are also aviableoption aspharmacotherapy forATS dependence. viruses, and engagement in criminal activity (McKetin & McLaren, 2005), suggesting agonist blood-borne to exposure sharing, needle as such harms,risks and similar face heroin and ATS2010). of Usersal., et (Kimber mortality of risk and behaviours injecting reducing as well as 2009), al., et (Mattick treatment drug in people retaining and useheroin reducing in effectiveness demonstrated has methadone investigation, rigorous of decades Through morbidity and mortality, and criminal activity associated with opioid use (McArthur, 1999). therapies. Methadone was introduced into Australia in 1970 in response to concerns about because the most effective pharmacotherapies for opioid and nicotine dependence ATS dependence of treatment the in areinterest particular agonist of are pharmacotherapies Agonist ence andincreases engagementandretention intreatment. reinforcing (that is, activate the reward pathway), which usually improves medication adher potential for abuse. Agonist medicines also offer the advantage of being inherently positively drug use by delivering a known and measurable dose, a legal and regular supply, and reducedusersillicit dependent comparisonadvantagesto for in some offer They patches). nicotine (e.g. dependence tobacco and buprenorphine) agonist opioid partial the and methadone agonist opioid the (e.g. dependence opioid treat to used currently are medicines Agonist - 5 Introduction - of the amphetamine molecule and a 2 is an atypical, non-tricyclic antidepressant and smoking cessation aid thought to to thought aid cessation smoking and antidepressant non-tricyclic atypical, an is belongs to a relatively new class of wakefulness-promoting agents known as Isomers are molecules that have the same molecular formula as each other but differ in the the same molecules that have are Isomers the molecules means atom, while dextrorotatory central the around arranged are way the atoms affects the pharmacological activity light to the right (such rotation the plane of polarised rotate of molecules).

2 apnoea. The pharmacology of modafinilis complex and the exact mechanism of actionis appears modafinil that found has research recent but 2006), Feifel, & (Ballon known yet not Modafinil associ- disorder sleep of for narcolepsy, the treatment approved it is In Australia eugeroics. ated with shift work, and excessive daytime sleepiness associated with obstructive sleep effect and antidepressant properties (Brensilver, Heinzerling et al., 2012), probably brought brought probably 2012), al., et Heinzerling (Brensilver, properties antidepressant and effect about by restoring depleted of levels dopamine (Rau et al., 2005), and has been approved cessation. smoking and disorder, seasonal affective of depression, for the treatment act through noradrenaline–dopamine re-uptake inhibition. It also acts as a nicotinic acetyl- nicotinic a as acts also It inhibition. re-uptake noradrenaline–dopamine through act withdrawal amphetamine reducing in role its for considered is It antagonist. receptor choline symptoms that are associated with dopamine depletion. Bupropion has a mild stimulant of monoamines into the synapse, thereby increasing concentrations of monoamines at the concentrations of increasing monoamines into the synapse, thereby synaptic cleft. Bupropion pharmacotherapy among dependent ATS users. Methylphenidate primarily blocks re-uptake re-uptake blocks primarily Methylphenidate users. ATS dependent among pharmacotherapy transporters, resulting in higher levels of monoamines at the synaptic cleft (Grabowski, Shearer, Shearer, (Grabowski, cleft synaptic the at monoamines of levels higher in resulting transporters, noradrenaline of release cause also dexamphetamine of doses Higher 2004). Negus, & Merrill (Howell & Kimmel, 2008). serotonin and dopamine and, to a much lesser degree, - for treat inhibitor approved re-uptake a Methylphenidate dopamine is and noradrenaline replacement a as trialled been also has and disorder; hyperactivity deficit attention of ment of being able to be provided in a known and controlled dosage, similar to opioid–agonists similar to in opioid–agonists a dosage, of known being and able controlled to be provided monoamines endogenous to similar structurally is Dexamphetamine dependence. opioid for dopamine (noradrenaline, and serotonin), competing with them for uptake at monoamine dependent ATS users in Australia and elsewhere. Dexamphetamine primarily increases release release increases primarily Dexamphetamine elsewhere. and Australia in users ATS dependent of monoamines. Dexamphetamine is a functional agonist of methamphetamine, meaning it produces similar pharmacological effects to methamphetamine, but has the advantages Dexamphetamine is the stereoisomer dextrorotatory among psychostimulant drug that for is approved pharmacotherapy the treatment of attention deficitreplacement hyperactivity a as trialled been has It narcolepsy. and (ADHD) disorder They are both structually similar to methamphetamine and both have similar effects to meth to effects similar have both and methamphetamine to similar structually both are They on primarily act medicines Both systems. neurotransmitter important these degree. on amphetamine lesser a to often latter the pathways, noradrenergic on and pathways dopaminergic the dependence. Dopamine depletion is a hallmark of ATS dependence and withdrawal. Two methylphenidate. and dexamphetamine are agonists functional are that pharmacotherapies Dopaminergic agents Dopaminergic - noradrena and serotonin dopamine, the neurochemistry, ATS in roles primary their to Due for ATS trials medicine treatment of agonist for a range been the targets have line systems 6 Medication treatment options for amphetamine-type stimulant users self-administration in animal studies, sparking interest in its ability to reduce ATS use among regulation of presynaptic autoreceptors. Fluoxetine was found to reduce methamphetamine down to attributed being effects longer-term with cleft, synaptic the at levels serotonin increasing therebyinitially neuron, the into serotonin of preventinguptake by work SSRIs Fluoxetine serotonergic agonists formethamphetaminedependencetreatment (Rose&Grant, 2008). useof the depression,providingrationalefor of a that to similar drawalsymptomsappear synaptic cleft would reduce ATS use. In addition, a wide range of methamphetamine with- the at serotonin of increase an if investigate researchersto led which consumption, mine serotonergictransmissionblocking that shownampheta- haveincreases studies Preclinical Serotonergic agents This medicineis notcurrently available inAustralia. effect. stimulant short-lived a exerts and noradrenaline, extent lesser a to and dopamine, of re-uptake the inhibits selectivelyantidepressanttricyclic that atypical an is Amineptine well (Zolkowska etal.,2009). mechanismsnon-dopaminergichave as does it though dopamine, extracellular in increase an to leading and re-uptake its transporter,inhibiting dopamine the on primarily act to dependent users and is currently being investigated foramong ATS of the effects rewardingtreatment subjective the reducing of in alcohol effectiveness its use determine to disorders. and vomiting associated with radiotherapy being used to treat malignancy. It has beendopamine releasetrialled (Johnson, 2007). It is approved in Australiacortico-mesolimbic reduce for theindirectly managementmay of antagonist nausea receptor 5HT3 a that hypothesised isneurons, it dopaminergic cortico-mesolimbic through act stimulants many As function. Ondansetron serotonin depletion. with withdrawal amphetamine of association the of because symptoms withdrawal ATS of treatment the for trialled been has It antidepressant. tetracyclic a as classified be also can mirtazapine Structurally,2001). Leinonen, & (Anttila serotonin and noradrenaline of the treatment of major depressive disorders. It is thought to work by enhancing the release Mirtazapine participants. serotonin at the synaptic cleft, was considered a valid target of investigation among human levels of increases which sertraline,therefore ATS; more self-administer to animals caused signalling serotonin inhibited that showed studies disorders.dysphoricpremenstrual Early and disorders anxiety social disorder, depressive major of treatment the for Australia in Sertraline is an antidepressant of the selective serotonin re-uptake inhibitor class, approved humans. is an antidepressant of the selective serotonin re-uptake inhibitor (SSRI) class. (SSRI) inhibitor re-uptake serotonin selective the of antidepressant an is is a noradrenergic and specific serotonergic antidepressant used primarily in primarily used antidepressant serotonergic specific and noradrenergic a is is a serotonin receptor antagonist and modulator of cortico-mesolimbic dopamine - 7 Introduction - - agonists mediating B receptors. Baclofen is primarily Baclofen is receptors. B receptor. Through its action on the GABAergic A is an anticonvulsant (anti-epilepsy) drug that showed promise in the treat is a GABA agonist and anticonvulsant that increases GABA concentrations in is a GABA antagonist available for injection only and used as an antidote in the the in antidote an as used and only injection for available antagonist GABA a is (Gamma Vinyl GABA or GVG) is an analogue of GABA (but not a receptor agonist) agonist) receptor a not (but GABA of analogue an is GVG) or GABA Vinyl (Gamma impaired through chronic ATS exposure, in the GABA system. exposure, ATS chronic through impaired Flumazenil treatment of benzodiazepine It overdose. was thought to play a role in restoring balance, vigabatrin has Australia been in shown to prescribed block reinstatementis It of drug-related2009). behaviors,al., suggestinget (DeMarco medication prevention relapse a as promise other medicines. by of epilepsy that has not been successfully controlled for the treatment Vigabatrin that has been shown to minimise the rapid rise of dopamine, and associated behaviours, metham- of effects pharmacological reduce to vigabatrin of ability The use. ATS following studies, preclinical In use. methamphetamine reduce may it how be to thought is phetamine topiramate topiramate is indicated only for the treatment of epilepsy in adults and aged children two headaches in adults. of migraine and the prevention and over, years treatment is not clear, topiramate is known to facilitate GABAergic transmission through depressing by a non-benzodiazepine system site onreward the the GABA on effect an have may topiramate that possible is it pathway, Australia, In 2012). al., et (Elkashef pathway mesolimbic the along transmission dopaminergic Topiramate ATS for usefulness its into investigations prompting thus use, cocaine and alcohol of ment methamphetamine for work may topiramate how for mechanism proposed the While users. treatment of refractory neuropathic pain not controlled by other drugs. Results from studies studies from Results drugs. other by controlled not pain neuropathic refractory of treatment showing gabapentin reduced craving for cocaine prompted interest in its role in treating methamphetamine dependence. Gabapentin - devel Originally GABA-transaminase. of inhibition via possibly system, nervous central the oped it for can be the also under of used treatment authority epilepsy, for in the Australia ing effects of ATS (Cousins, Roberts & de Wit, 2002). Therefore, a number of GABAergic dependence. ATS in treating role for their potential investigated been medicines have for GABA of GABA and an agonist a derivative Baclofen is transmission along the mesolimbic dopamine system, which is thought to reduce the reward the reduce to thought is which system, dopamine mesolimbic the along transmission GABAergic agents GABAergic inhibit- in role key a play to found been has system (GABA) acid gamma-aminobutyric The mechanism possible One 2010). Slesinger, & (Padgett brain the in transmission synaptic ing to reduce the effects reinforcing of ATS and craving is through GABA used to treat involuntary muscle spasm in multiple sclerosis and spinal lesions and is being is and lesions spinal and sclerosis multiple in spasm muscle involuntary treat to used disorders. of alcohol use the treatment for investigated 8 Medication treatment options for amphetamine-type stimulant users Atypical (second-generation) antipsychotics states anddelirium,wastrialledforitseffectiveness totreat ATS-induced psychosis. Haloperidol is an older antipsychotic used in the treatment isof a schizophreniabutyrophenone derivative andand has acutepharmacological effects psychoticsimilar to the phenothiazines. Haloperidol is a dopamine antagonist of the typical (first-generation) antipsychotic class. It to treat psychosis associatedwithamphetamineuse. other substances such as opioids. As noted below, dopamine antagonists are commonly used with usedapproach‘antagonist’ typical the in useful not are agents these that suggesting 2008), Grant, & (Rose haloperidol or risperidoneantagonists dopamine the by reduced be to appear ATSusers.not medicines,with ATSdo of However,of class effects euphoric the antipsychotics the as such pharmacotherapies, antagonist dopamine trialling for basis the encies other than ATS (such as naltrexone for alcohol and opioid dependence) has provided depend- drug of treatment the in pharmacotherapiesantagonist of studies from Evidence eventual eliminationofdrug-using behaviours (Herin,Rush &Grabowski, 2010). the in resulting concern, of drug the of effects reinforcing, therefore and rewarding, the 2012).al., et usefulnessThe antagonistof ismedicines block to ability their be to thought its effects, but unlike agonists, these medicines exert no active effect (Brensilver, Heinzerling Medicines that work as antagonists bind to the same receptors as the drug of concern and limit Dopamine antagonists for ATS-induced psychosis. stabilisers for treating acute mania associated with bipolar 1 disorder. Trialled as a treatment mood therapyadjunctiveto as and schizophrenia for treatment a approvedAustraliaas in Risperidone tiveness intreating mooddisorders and ATS dependence. in Australia for the treatment of schizophrenia and bipolar 1 disorder. Trialled for its effec- antagonist,approveddopamine serotoninand antipsychoticand atypical isan Quetiapine trialled foruse inATS-induced psychosis. is structurally similar to clozapine, but is classified as a thienobenzodiazepine and has been approved in Australia for the treatment of schizophrenia and related psychoses. Olanzapine Olanzapine depression; ithasbeentrialledasatreatment forATS-induced psychosis. clinical disorderand bipolar schizophrenia, of treatment the in used propertiesdepressant Aripiprazoleis agonistdopamine partial a antipsychotic atypical and anti - additional with tion andextrapyramidal side effects. medicines, allowing more normal dopamine transmission and less effect of hormones, cogni more rapid dissociation from the dopamine receptor than the first-generation antipsychotic (movement) side effects and constipation. The reduced side-effect profile is attributed to a extrapyramidal of degree lesser the to due haloperidol as such antipsychotics typical from differ risperidone and quetiapine olanzapine, aripiprazole, as such antipsychotics Atypical is an atypical antipsychotic. Olanzapine is a serotonin–dopamine antagonist antagonist serotonin–dopamine a is Olanzapine antipsychotic. atypical an is is a dopamine antagonist of the atypical antipsychotic class of medicines, medicines, of class antipsychotic atypical the of antagonist dopamine a is - 9 Introduction - - is a long-acting calcium ion antagonist used as an antihypertensive and in is a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, which which agonist, partial receptor acetylcholine nicotinic alpha4beta2 selective a is is an opioid receptor antagonist that exerts effects by blocking the effects of stimulates nicotine receptors more weakly than nicotine. As a partial agonist, it both reduces reduces both it agonist, partial a As nicotine. than weakly more receptors nicotine stimulates products, tobacco other and cigarettes of, effects pleasurable the decreases and for, cravings making it a candidate for trials among ATS In users. Australia, it is prescribed as an anti- aid. smoking Varenicline Nicotinic antagonist smooth muscle, amlodipine causes vasodilation, reducing vascular tone and blood pressure. pressure. blood and tone vascular reducing vasodilation, causes amlodipine muscle, smooth blocking by use ATS of effects rewarding the reducing in role a play to thought is Amlodipine central dopamine pathways in the brain. Calcium-channel blockers have been proposed as for a treatment methamphetamine of dependence because their ability observed to reduce the effect of dopamine in central antagonising effects of methamphetamine, by subjective et al., 2008). (Johnson pathways dopaminergic Calcium-channel blockers Amlodipine the treatment of angina pectoris. By blocking calcium ion influx selectively onvascular amphetamine and be involved in cravings to use. A number of medicines have been trialled been have medicines of number A use. to cravings in involved be and amphetamine users. among ATS cravings reduce to to determine their effectiveness Pharmacotherapies to reduce craving to reduce Pharmacotherapies meth of effects rewarding the mediate to thought are midbrain the in pathways Dopamine been examined for its role in tempering the rewarding effects of ATS among dependent users. dependent among ATS of effects rewarding the tempering in role its for examined been hol and limit its rewarding effects when consumed. Opioid receptors are located on dopamine dopamine on located are receptors Opioid consumed. when effects rewarding its limit and hol cell bodies, partially modulating dopaminergic & effects Cortes, Schwartz, Pollard (Llorens has 1979). been to also Stimulant shown change administration in opioid density receptor drug of reinforcement with associated be to known region brain a accumbens, nucleus the also has naltrexone such, As 1996). Cox, & Clock Buzas, Coughlin, (Azaryan, administration Naltrexone in the management of opioid in Australia for use authorised It is and other opioids. heroin alco for cravings reduce to shown been has Naltrexone dependence. alcohol and dependence Opioid antagonists binding by opioids occurring) (naturally endogenous of effect the block antagonists Opioid a opioids, endogenous blocking by that, hypothesised is It brain. the in receptors opioid to of methamphetamine. properties on the reinforcing change can be effected 10 Medication treatment options for amphetamine-type stimulant users alcohol and other drug treatment sector generally, and specifically for the treatment of ATS the within pharmacotherapy of use the about views of range broad a is There them. with gap in evidence-based treatment options for clients and the health professionals who work important an leaving withdrawal, or dependence ATS of treatment the for internationally or Australia in approval widespread have medications no far, so efforts research Despite Purpose ofthis review monly claiming antioxidant and liver-protecting effects. It is also used as a cough medicine. com supplement, dietary a as Australia in counter the over sold is It cravings. drug with and glutathione, and is thought to have a role in reversing glutamate dysfunction associated N-acetyl cysteine, commonly known as NAC, is the precursor to both the amino acid L-cysteine craving forcocaine,andwastherefore trialledamongdependentATS users. regions. Used as adjunctive therapy for Parkinson’sbrain certain in disease,levels acetylcholine it and also serotonin showeddopamine, norepinephrine, promise increase to in reducing neuroprotectivehaveand propertiesto thought is and stroke acute with associated ments Citicoline Other medicines questions: The reference group that guided the conduct of this review developed a number of research research effortsinAustralia. future of concentration for areas of identification and guidelines clinical of updating and patients. The review is designed to help to guide the next steps, including the development tions, including which medicines show potential, under what circumstances,condi related and with and which dependence ATS of treatment the in medicines for role potential the articulate to was treatment ATS for pharmacotherapies for evidence the of review this of breadth of opinion on the role and function of pharmacotherapy for this group, the purpose approvalof ATSlack userswith the routine medicines of usethe for of context and the In dependence. 1. 4. 3. 2. What are the advantages and disadvantages of each of the medication treatment options? ment interventions? What are the medication treatment options and what is their relationship to other treat the role Australian research mightplay? What are the areas of promising research for the treatment of dependent ATS users and internationally, forthetreatment ofdependentATS users? as well as Australia within available, currently are options treatment medication What is a naturally occurring compound shown to reduce some of the functional impair - - - - Methods 11

traditional systematic review works best when there are large numbers of studies with

search search period was January 1997 to January Hand-searching2013. of specific papers also identified some additional studies. Search terms were developed based on the aims and scope of the review. A combination of combination A review. the of scope and aims the on based developed were terms Search title and text the in words and terms keyword terms, thesaurus) database other (and MeSH were used. Groups of key terms were used for searches, then systematically combined for searched databases The databases. all across questions clinical of sets various the exploring The Reviews. Systematic of Database Cochrane the and Embase PsycINFO, MEDLINE, were: Search strategy Search weight of the evidence is for or against the use of a medicine), a or realist meta-narrative review is designed to examine similarities and differences in the data and to look beyond (Wong et al., 2009). ‘in what circumstances’ ‘what’ to ‘why’, ‘how’, ‘for whom’ and varied research outcomes. research varied either the the evidence as ‘all-or-nothing’ (that is, and interpreting Rather than presenting of psychological treatments or policy interventions). Although the efficacy and effectiveness effectiveness and efficacy the Although interventions). policy or treatments psychological of Pawson, & Greenhalgh (Wong, intervention’ ‘simple a considered generally are medicines of 2009), the complexity of methamphetamine use has resulted in the reporting of widely (Pawson, Greenhalgh, Harvey & Walshe, 2005) is a pragmatic method of understanding a diverse and disparate literature. Meta-narrative reviews are typically used for distilling in areas which may there be (that multiple multiple is, components, complex interventions evaluation as such intervention, the of application the in variability natural or groups target similar methodologies and outcome measures. similar methodologies methods, when literature the interpret researchers help to emerged has review of form newer A review or realist 2012) (Potts, review A meta-narrative widely. and outcomes vary measures review in that the search method and the evaluation of the articles are explicit and replicable. replicable. and explicit are articles the of evaluation the and method search the that in review Furthermore, it allows a systematic sorting of the evidence to answer specific questions. A systematic search method as the primary vehicle to include all relevant results in a summary summary a in results relevant all include to vehicle primary the as method search systematic can review systematic A question. research specific a answer to effort an in literature the of general a from differs and studies), case and qualitative (including study of type any include This review was undertaken usingthorough a a use systematic reviews review methodSystematic coupledfindings. of with interpretation a the modified to approach meta-narrative Methods 12 Medication treatment options for amphetamine-type stimulant users Inclusion andexclusion criteria The exclusion criteriawere: The inclusion criteriawere: data. Details ofthesearch, screening andreview procedure are shown inFigure 1. ers. Elements from the meta-narrative approach were used in the interpretation of the review Qualitative analysis, synthesis and interpretation of the data were undertaken by two review Analysis by asinglereviewer andcheckedentered intoasummarytableby asecondreviewer. animal studies, participants without ATS dependence). Data from each article were extracted second screen, all studies that did the At not ATS. to meet related not were inclusionthat studies all excluded criteria reviewer one screen, first were the At excluded (e.g. laboratory and Screening andextraction • • • • • • • • • • • • studies ofpharmacotherapy responses toacutetoxicity. healthy volunteers orused dependentvolunteers inalaboratory setting) studies that included primarily non-treatment appropriate participants or contexts (e.g. studies thatincludedprimarilynon-dependentparticipants qualitative studiesandgeneral reviews studies published priorto1997 non-English manuscripts animal studies levels ofevidence). Council Research Medical and Health (National studies intervention above or IV Level manuscripts inEnglish orwithavailable English translation articles published between1997and2012 (last15years) adult studies human studies

used - Methods 13 52 2021 56 158 other sources: Number of citations identified through Number of citations identified Final review Quality check Second screen First screen 6537 removed): 2179 Number of studies assessed for quality: Number of studies included in final review: Number of studies excluded at second screen: Number of citations (duplicates & irrelevant records Figure 1: Search, screening and review procedure and review screening 1: Search, Figure (including duplicates): Number of citations retrieved through database searching Number of citations retrieved 14 Medication treatment options for amphetamine-type stimulant users See summaryevidencetablebeginningonpage48fordetails ofthis group ofstudies. Withdrawal from amphetamines Amphetamine andmethamphetamine Detailed findings tion aboutitsabuse potentialanditis currently unavailable inAustralia. 300 have some effect during withdrawal and may also assist with relapse prevention. Although Of the four medicines examined, modafinil, mirtazapine and dexamphetamine appear to medicines are commonlyrecommended inclinicalguidelines. ment of sleep disturbance or agitation among ATS users in withdrawal, even though these No evidence was found for the use of benzodiazepines or other medicines for the manage active treatment andplacebogroups improved. both placebo, to compared effects non-significant showed medicines Where reported. The results are not conclusive but, despite small sample sizes, some positive results were Overall summary withdrawal program. supervisedretainingusersfutureresearcha assistin area for in to worthy a be thismay Given ATS treatment has a high drop-out rate and a high relapse rate during withdrawal, further research is needed to confirm the effectiveness of these medicines for withdrawal. promise, show dexamphetamine and modafinil mirtazapine, Although medicines. these favouragainst of samplestrongin or efficacy of either of the sizes,lack evidence a and small with most studies, of number small a However,were there treatment. ATS in use for safe be to appear medicines these individuals dependent heavily and moderately both among that suggesting studies, these in reported were events adverse serious No In summary, theresearch shows that: such asbenzodiazepines, whichare used toreduce agitation. withdrawal, ATS for pharmacotherapyrecommended commonly other support to exists is strategies available for methamphetamine withdrawal and merit further investigation.symptom-management of range the in role potential a haveThere may dexamphetamine and mirtazapine modafinil, that suggests limited, review,although this from evidence The • • • evidence for the use of these medicines, which is more evidence than currently than evidence moreis which medicines, these of use the for evidence some symptoms insomeparticipantsover aperiodof2–8weeks. withdrawal reducing in effectiveness demonstrated dexamphetamine 60–110 of mg did notproduce convincingeffects doses lower period; day 7–10 a over participants some in symptoms withdrawal ing 400 some participants over a 14-day period; lower doses did not produce convincing effects 60 mg of amineptine (the fourth medicine) appears to be effective, there is some ques-

mg of mirtazapine demonstrated effectiveness in reducing withdrawal symptoms in

mg of modafinil demonstrated effectiveness, when tolerated by patients, in reduc - Detailed findings 15 - Future Future clinical guidelines should detail the circumstances under which these medicines could and be for used, whom, and the medical that monitoring would strategies ensure use. their safe the longer-term benefits of maintenance medication prescribed during withdrawal have not not have withdrawal during prescribed medication maintenance of benefits longer-term the in any studies. been examined that these medicines remain a possibility for assisting with symptom management during and merit further investigation. withdrawal resulted dexamphetamine and improvements neuropsychological in resulted also Modafinil although prevention, relapse for implications have could which of both craving, reduced in symptoms (but not drug use). All of the studies had very small sample sizes. sample small of the studies had very All (but not drug use). symptoms adverse serious no with given doses of range wide a at tolerated well were medicines four All suggesting studies, some from effects clinical positive of indication some and reported effects in withdrawal or other measures compared to placebo, with others finding significant dif- et al., 2005) etand al., modafinil (McGregor of mirtazapine in (Kongsakon favour ferences withdrawal of severity in reduction significant a showed studies dexamphetamine Both 2008). were also reviewed. also were two and 2013) al., et (Lee study modafinil one with mixed, were studies these of results The differences no finding 2008) al., et McGregor 2008; al., et (Cruickshank studies mirtazapine amineptine (Jittiwutikan, Srisurapanont & Jarusuraisin, 1997; Srisurapanont, Jarusuraisin & Jittiwutikan, 1999; 2010) Srisurapanont et al., al., andet 2001) two Longo dexamphetamine maintenance 2011; al., et (Galloway outcomes symptom withdrawal reported that trials sakon, Papadopoulos & Saguansiritham, 2005), one studied modafinil (Hester, Lee, Pennay, Pennay, Lee, (Hester, modafinil studied one 2005), Saguansiritham, & Papadopoulos sakon, from the same Nielsen study; & 2010 Lee Ferris, et al., one 2013), trial modafinil involved Mitchell, Wickes Srisurapanont, & and White, mirtazapine 2008), (McGregor, studied three for withdrawal, and two studies of maintenance medicines, which also measured withdrawal withdrawal measured also which medicines, maintenance of studies two and withdrawal, for review. included in this were symptoms, Of the nine included studies, two examined mirtazapine (Cruickshank et al., 2008; Kong Shoptaw and colleagues found mixed results for mirtazapine. Since then, another five relevant relevant 2001). Both five found another favourable then, results Since overall formirtazapine. twofor studiesresults involvingmixed amineptine;found colleagues and and Shoptaw papers have been published. In total, seven papers from six separate studies of medicines Summary of literature reviewed Summary of literature Collaboration Cochrane the from researchers by conducted been have reviews systematic Two Kittirattanapaiboon, & Jarusuraisin Srisurapanont, 2009; Ling, & Heinzerling Kao, (Shoptaw, 16 Medication treatment options for amphetamine-type stimulant users Modafinil on evidenceforotherillicitdrugwithdrawal. guidelines should carefully consider recommendations for the usethese of revisionsof Future medicines supervision. under thatuse arefor 1996) based Thornton, & Dunlop Lintzeris, 2009; al., et Kenny 2008; al., et Dunlop 2004; Muhleisen, & Lee Hocking, Dunlop, (e.g. in withdrawal, although benzodiazepines are commonly recommended in clinical guidelines management of sleep disturbance, agitation or other the psychiatricfor medicines symptoms other among or ATS usersbenzodiazepines of use the for found evidence no was There and whilemeta-analysis is possiblewithsmall numbers ofstudies, itis lessreliable. to clarify whether differences exist but there were only one or two studies of each medicine, ences that may be clinically significant in a withdrawal situation. A meta-analysis may help largest had 60 participants. At these sample sizes it would be difficult to detect small differ All of the studies had relatively small sample sizes: the smallest had 19 participants and the minority ofpatients. a in headache and nausea as such effects side mild were there medicines, most with As conditions. supervised under withdrawal during use to safe generally are medicines these that suggesting reported, adverseeffects serious no were there and symptoms withdrawal In each of the reviewed studies, those taking the active medicines improved on measures of Meta-narrative analysis study. The larger dose of 400 of study.dose larger The (Hróbjartsson & Gøtzsche, 2010) and there may have been a placebo effect in the McGregor Placebo medicines have been shown to positively study. influenceopen-label patients’ an self-reported was symptomsformer the addition, In response. in differences the explaining This study used higher doses of modafinil (400 McGregor et al. (2008) found significant differences in withdrawal symptoms using modafinil. size forthis studywassmall. been in the modafinil group, resumed ATS use, suggesting some benefit. However, the sample treatment early, most of those who had been in the placebo group, but not those who had symptoms or on retention in withdrawal treatment. Of the participants who left withdrawal withdrawal on benefit no (2013) found al. et Lee functioning. executive and memory ate et Hester and symptoms, withdrawal on effects significant reported (2008) al. et McGregor modafinil, with treatment after outcomes withdrawal reported that papers three the Of result inabetteroutcome.

al. (2010) reported significant effects on cognitive functioning, specifically on immedi on specifically functioning, cognitive on effects (2010) al. significant reported mg did not produce significant side effects but appeared to appeared but effects side significant produce not did mg

mg) than Lee et al. (2013) (200

mg), possibly - - Detailed findings 17 - mg. mg.

mg. Larger doses Larger mg. mg and found significant effects of

mg. McGregor et al. (2008) reported large large reported (2008) al. et McGregor mg.

mg, found a non-significant trend (with a small sample size) in reduction in size) sample small a (with trend non-significant a found mg, need for more detailed and approaches standardised to the reporting of pharmacotherapy assist may studies multiple of results the pooling meta-analysis a start, a As required. is trials work. the scope of the current was beyond This in clarifying outcomes. and outcome means, in enough detail to assist in clinical decision making. This suggests the the suggests This making. decision clinical in assist to detail enough in means, outcome and rates of relapse immediately after withdrawal (50%), it appears to be an area that would et al., 2005). et al., 2005; McKetin efforts (Brecht research intensive more benefit from sizes suggest sample and in The that small results variability low the from studies suffered not did studies Many results. conclusive more show to needed are studies larger and power, report important such factors, as doses average (where a variable dose schedule was used) lighting a sizeable research gap. Given the poor treatment completion rates (50%) and high and (50%) rates completion treatment poor the Given gap. research sizeable a lighting et al., 2009; Lintzeris et al., 1996). These guidelines are based on recommendations for the management of other drug withdrawal, which reflects the paucity ofresearch into the withdrawal. pharmaceutical management of ATS found, high- were for amphetamine withdrawal few studies of pharmacotherapy Relatively Research implications Research of medicines for the management a range guidelines that recommend numerous are There Kenny 2008; al., et Dunlop 2004; al., et Dunlop (e.g. users ATS in symptoms withdrawal of Amineptine results the of distilling further no medicine, a as available currently not is amineptine Since was undertaken. treatment of ATS withdrawal in moderate butusers, further research is required. A meta- may be possible. analysis of withdrawal symptoms among mainly years) long-terminjecting (11 methamphetamine users. Although limited, these results suggest that dexamphetamine is promising for the ment entry. ment Galloway entry. used a et dose al. of (2011) 60 dexamphetamine in reducing withdrawal symptoms and craving among mainly moderate using (2010), al. et Longo and month), previous the in days (17 smokers methamphetamine 20–110 of dose a Dexamphetamine The two studies of dexamphetamine were not originally designed as withdrawal studies but did measure withdrawal symptoms among people who were not abstinent at treat appeared appeared to produce larger effects with no significant adverse eventsreported. McGregor effect. placebo some been have may there and study open-label an conducted (2008) al. et reported significant effects of mirtazapine at 15–30 at mirtazapine of effects significant reported 60 at modafinil) not (but usual as treatment over mirtazapine of benefits significant and 30 at effects non-significant and small reported (2008) al. et Cruickshank Mirtazapine (2005) al. et Kongsakon not. did one and benefits positive showed studies mirtazapine Two 18 Medication treatment options for amphetamine-type stimulant users See summarytablebeginningonpage58fordetails ofthis group ofstudies. Treatment foramphetaminedependence some people, and there were few adverse events reported. Most of the studies were con- to benefit some users,offer methamphetamine to dependent appear optionsfor do but Without further research, these medicines cannot yet be considered as routine treatment effects intheliterature reviewed: The following medicines appear to be well tolerated and showed some significant positive a treatment area initsrelative infancy, butnowlarger RCTs are required. studies.Thissmaller-scaleisfeasibility areconsistent all date to with conducted studies and bupropion (four, all RCTs). The evidence is sparse for the remainder. In addition, the RCTs) three including (five, modafinil byRCTs), followed four including (seven, number the subject of relatively few studies. Dexamphetamine has been the subject of the greatest been has medicine each examined, pharmacotherapies many been have there Although relapse amongdependentmethamphetamineusers. preventing or use ATS reducing in effectiveness of evidence consistent demonstrated None pharmacotherapies. potential 18 examining identified, were studies Thirty-nine Overall summary most from thesemedicines. on treatment matching and identifying particular subgroups of ATS users that may benefit unknown. As these medicines showed some benefits, future research efforts could focus is medicines these of use long-term safe and effective the so weeks, 8–12 over ducted • • • • • and 54 mgfrom week3(optimaltimefordailydosingwas unspecified). 18 of dose starting a be to seems dose Methylphenidate may improve retention in treatment and reduce use. The most effective most effective dose was 50 The ATS. use to craving reduce and treatment in improveretention may Naltrexone men andforthosewithalighterpatternofATS use. doses (150 increasing to 300 150 of dose starting a reportedeffectivewas dose most The month). per use days (<18 users ATS ‘lighter’ by use ATS reducing in effective was Bupropion morning tolimitsleep disturbance. 400 was dose effective most The medicine-compliant. were Modafinil was found to be superior to placebo in reducing ATS use among those who 100 mg perdaytakeninthemorningtolimitsleep disturbance. be to literatureappears the in reported dose effective most The retention.treatment Dexamphetamine reduced the severity of dependence in some participants and increased mg morning and 150

mg per day after three days taken either in the morning or in divided

mg per day (optimal time for daily dosing was unspecified). mg evening). Bupropion may be especially useful for

mg increasing to 36 to increasing mg mg per day taken in the in taken day per mg

mg in the second week week second the in mg mg per day per mg Detailed findings 19 vigabatrin (evidence of adverse effects) vigabatrin (evidence of adverse effects) (evidence of adverse sertraline Prometa™ protocol of combination flumazenil and gabapentin (evidence of adverse effects). baclofen (limited evidence of benefit) gabapentin (limited evidence of benefit) benefit) (limited evidence of ondansetron amlodipine (limited evidence of benefit) effects) (evidence of adverse aripiprazole rispiridone varenicline. mirtazapine fluoxetine topiramate • • • • • • • • • • • • • Overall, Overall, the studies showed variable outcomes and some results were conflicting, even while poor sizes, Many study sample had retention small study conditions. under robust to barriers common were prescribed as medicines take to participants many of failure and users from differ that patterns in ATS use to tend Australians results. high-quality gaining in other countries (e.g. higher rates of injecting), and as most of the evidence has been effectiveness the examine to needed is research further studies, international from gained conditions. local under adults ATS-dependent treating for promise show that medicines of There There were a number of other medicines that showed promise and, hence, may also be further research: good candidates for Other medicines showed either no benefit or an unacceptable effect adverse profile and research: or for future clinically do not appear to be of value 20 Medication treatment options for amphetamine-type stimulant users with a large number of medicines, the research into pharmacotherapies for amphetamine amphetamine for pharmacotherapies into research the medicines, of number large a with studies were RCTs. Thus, although studies have been accruing over a long period of time and reports (dexamphetamine (n=7), modafinil (n=5) and bupropion (n=4)), and not all of those the subject of only a few studies, with only three medicines having more than three published Although a wide variety of medicines have been trialled, most individual medicines have been and themedicalmonitoringstrategies thatwouldensure theirsafe use. should detail the circumstances under which these medicines could be used, and for whom, may be useful in further assessing the viability of these medicines. Future clinical guidelines circumstances with specific patients under well-monitored conditions feasible. Meta-analysis sample sizes. But a number did show some promise, which may make their use in particular abstinence that were strong enough to recommend their routine use, probably due to small or use ATS reduced of variables main the across effects showed medicines these of None produced significantadverse effects, even inpatientsseverely dependenton ATS. medicines these reported, doses the at that, evidence no was overallthere but medicines, effects and risks, side some and on with occasion come particular individualsmedicines may All have events. unusual adverse responsesserious no to some reported studies these of pharmacotherapies. Thirty-five potential 18 examining identified, were studies Thirty-nine Summary ofliterature reviewed were significantly more likely to reduce drug use (Anderson et al., 2012; Shearer et al., 2009). Modafinil: et al.,2007)butnotinasecond study(Milesetal.,2013). Methylphenidate (Longo etal.,2010; Shearer etal.,2001). dependence of severity the reduce may and sessions,counselling at attendance and ment Dexamphetamine of participants. Nonereported anyserious adverse events. report and has shown some benefits over placebo on some variables or within some groups peer-reviewed one than more of subject the been has medicines these of Each research. showed equivocal but promising results, suggesting they may be effective targets for further naltrexone) and bupropion modafinil, methylphenidate, (dexamphetamine, medicines Five Medicines showing somebenefitin randomised controlled trials Meta-narrative analysis four dexamphetamine randomised controlled trials numbered 60participants. has been a study with a very large sample size. For example, the largest sample among the pharmacotherapy; that is, they are case studies, open-label studies or feasibility RCTs. None dependence is in its relative infancy. Many of the studies are typical of early studies of any Two RCT studies showed that those who were compliant with taking the medicine was superior to placebo in reducing amphetamine use in one study ( showed benefit over placebo on secondary variables of retention in treat Tiihonen - Detailed findings 21 - Two open-label uncontrolled trials by the same research group (Meredith, has been the subject of only one study, an RCT, which showed significant One large double-blind multi-site RCT (Elkashef et al., 2012) showed topiramate topiramate showed 2012) al., et (Elkashef RCT multi-site double-blind large One One recent pilot RCT (Swanson, Shoptaw & Heinzerling, 2011) reported greater greater reported 2011) Heinzerling, & Shoptaw (Swanson, RCT pilot recent One One RCT study (Jayaram-Lindström, Hammarberg, Beck & Franck, 2008) found found 2008) Franck, & Beck Hammarberg, (Jayaram-Lindström, study RCT One A single double-blind RCT (Batki et al., 1999) found fluoxetine was not superior superior not was fluoxetine found 1999) al., et (Batki RCT double-blind single A retention rates and trends in favour of varenicline over placebo in reducing methamphetamine methamphetamine reducing in placebo over varenicline of favour in trends and rates retention with placebo. of abstinence compared duration and increasing use injectable risperidone on measures of methamphetamine use, craving, verbal memory and symptoms. psychiatric Varenicline: Risperidone: Cherrier & 2007; et Saxon, Meredith al., 2009) Jaffe, found Yanasak, in of and favour oral Topiramate: was ineffective among study completers in promoting methamphetamine abstinence but general increasing and dependence of severity and use reducing on placebo to superior was functioning. Fluoxetine: use, methamphetamine urinalysis-confirmed and self-reported both reducing in placebo to to the placebo group. compared group was lower in the fluoxetine but craving 50 per cent of participants took the medicine regularly as prescribed, suggesting it may be may it suggesting prescribed, as regularly medicine the took participants of cent per 50 their use. to reduce highly motivated for those who are useful more Mirtazapine decreases in methamphetamine use and sexual takingrisk Brensilver, (Colfax et al., 2011). than fewer But mirtazapine. of benefits potential the highlighted also (2012) al. et Johnson A number of medicines show promise but the number of studies is too small to draw conclu draw to small too is studies of number the but promise show medicines of number A n small single a either in so done have but benefits, some shown have them of Many sions. studies. non-RCT RCT study or one or more bupropion, methylphenidate and naltrexone are among the most promising medicines to date. to medicines promising most the among are naltrexone and methylphenidate bupropion, further research but require potential Medicines that may have These findings are consistent with, and were built that uponconcluded which by, a review 2012), by BrensilverShoptaw, et & Bholat al. Heinzerling, Grotheer, Johnson, (Brensilver, Naltrexone: group naltrexone the among retention better and craving reduced use, amphetamine lower RCT study found no differences. smaller to placebo but a second compared ated with a 90 per cent likelihood of treatment failure. They concluded that, in a visits clinical weekly three first the in samples urine drug-free two least at achieve to failure setting, the goal, When urine abstinence testing is may failure. for treatment a high risk represents success. likelihood of treatment help to indicate the in a month) (Elkashef et al., 2008; Shoptaw et al., 2008). In a re-analysis of two randomised randomised two of re-analysis a In 2008). al., et Shoptaw 2008; al., et (Elkashef month) a in Heinzerling controlled et trials of al. found bupropion, Brensilver, (2012) that the inability associ- was treatment of week first the in samples urine drug-free three least at produce to Bupropion appears to be associated with reduced methamphetamine use among men but days (<18 use of patterns ‘lighter’ with those among and 2008), al., et (Elkashef women not 22 Medication treatment options for amphetamine-type stimulant users Medicines withunacceptableside-effect profiles This report wasaconference abstract withlittledetailaboutthedirection ofanychanges. Amlodipine: One RCT (Batki et al., 2001) found no effect for amlodipine on any measures. significant) thantheplacebogroup. (non- outcomes poorer showed groups treatment The dependence. of severity or craving use, methamphetamine of measures on placebo to superior not was but participants by Ondansetron: compared tothelonghalf-lifeofATS maylimititsuse. in methamphetamineuse whencompared withplacebo,but the short half-lifeof baclofen tion. However, participants with greater medicine adherence showed a significant reduction superior to placebo overall on measures of methamphetamine use, craving or treatment retenBaclofen: and placebo. baclofen both to compared when retention or cravinguse, methamphetamine reducing in Gabapentin: Medicines withlimitedornoevidence ofbenefit of reduction. Inaddition, theprotocol is complextoadminister. have been a response to entering treatment, as the placebo group also showed a similar level Baron,2011).(Urschel,Hanselka& trial the of 1 decreasemay week initial pre-trialto The treatmentand groups, resultsthe although show largea decrease ATSin use from days30 gabapentin, ATS use steadily increased during the trial from day 1 to day 30 in both placebo gabapentin: and flumazenil Combination Zorick, Sugar, Hellemann,Shoptaw&London,2011). also showed poorer retention and more adverse events than placebo (Shoptaw et al., 2006; same data set). They showed increases in use during the trial period and one the ofof analyses(different sertraline of theseoutcomes the of analysesreports two wereThereSertraline: efforts should focus onmedicineswith greater promise. future benefits, researchfew with trial open-label small a was study this and impairment), vision permanent previously (including reported been have defects that given but defects, field visualunusual any show not did vigabatrin of study open-label single A Vigabatrin: samples andshowed aworsening ofsymptoms. events. Participants in the aripiprazole group produced significantly more positive ATS urine Aripiprazole: gabapentin (bothofwhichappeartoincrease amphetamineuse). and flumazenil combination of protocol Prometa™ the and sertraline and effects) adverse serious potentially have to appear which of (both vigabatrin and aripiprazole including effects, side unacceptable to due used be not should medicines some suggest results The One RCT (Heinzerling et al., 2006) found the GABA the found 2006) al., et (Heinzerling RCT One One double-blind RCT (Heinzerling et al., 2006) found no effect for gabapentin The subject of one trial that had to be discontinued because of serious adverse One RCT (Johnson et al., 2008) reported that ondansetron was well tolerated In one study of combination flumazenil and and flumazenil combination of study one In B agonist baclofen was not not was baclofen agonist - Detailed findings 23 further trials of mirtazapine, baclofen and topiramate, which showed but promise have been the subject of only one study each. studies that examine the potential relapse–prevention of these drugs in abstinent users supervised undergo patients all which in design discontinuation random a example, (for and ATS with from treated withdrawal are the medicine, target then one with- is group allocation) to random the medicine according from drawn of further methylphenidate, outcomes trials as in positive it one - showed study and rep required lication is currently reported in these studies were insufficient for meta-analysis, but access to in reported the these forcurrently studies insufficient meta-analysis, were would enable such an analysis of these analyses further details original data sets or of re-analysis some of the larger data sets or designing studies that identify subgroups from distinct as medicines these from benefit differential a show may which users ATS of as a whole the sample meta-analytic review of modafinil, dexamphetamine and bupropion studies; the data • • • • • with maintaining motivation is an important factor in optimising client outcomesclinical setting. in a Role of adherence with prescribed medicines with prescribed Role of adherence stud- Many low. was prescribed as medicines taking to adherence studies, these of most In ies found a between correlation and adherence better suggesting outcomes, that if any of these medicines are used, monitoring of adherence is important for ensuring effectiveness assistance that suggesting also high, very were rates attrition studies some In treatment. of Other considerations in the treatment of amphetamine dependence in the treatment Other considerations adherence may be useful. Contingency management shows promise in supporting adherence adherence supporting in promise shows management Contingency useful. be may adherence to the pharmaceutical protocol. At least one study noted the for requirement daily dosing so flexibleregimes more dosing could (Miles be adherence et may reduced al., have 2013), trials. clinical for future considered Many studies had small sample sizes, high drop-out rates and low medication adherence. Studies that examine ways to retain patients in pharmacotherapy treatment and improve goal across a spectrum of users. Further work should focus on areas of potential benefit and could include: Research implications Research methampheta- for pharmacotherapy a identify to undertaken been have studies Numerous or abstinence as the treatment in drug use reduction examined mine dependence. All have 24 Medication treatment options for amphetamine-type stimulant users Cultural issues effect intheresults thatis unlikelytobereplicated intheclinicalsetting. therapeutically beneficial (Kypri et al., 2007) and in some studies may haveis created itself a ceiling assessment that suggest to evidence is There protocol. the of part as procedures assessment intensive employed studies the of many that is factor complicating further A to beeffective forarange ofusers, includingthosewhoare dependent. shown been has intervention MI/CBT combined colleagues’ and Baker treatment. users in dependent for designed work individual and group involving intervention intensive an is al., 2005), have been shown to be effective for methamphetamine users. The Matrix Model session brief cognitive behavioural and motivational interviewing (MI) intervention (Baker et four- standard gold Australian the and States United the in extensively used 1995) al., et effect of the medicine itself. Psychosocial interventions, such as the Matrix Model (Rawson apparent effectiveness of the medicines being examined, making it difficult to determine the psychosocial interventions for both the treatment and placebo groups may have masked the pharmacotherapy.with treatmentstudies,sessionsvariedat between attendance Although Nearly all the studies utilised psychosocial interventions, some quite intensively, in conjunction Role ofpsychosocial interventions lighter users (e.g.<18days ofuse inthelast30days). did not show benefit overall, post-hoc analyses suggest that there may be some benefit for heavier users during treatment with bupropion compared with placebo. Although bupropion lighter users were nearly three times more likely to have a methamphetamine-free week than in urine quantitative methamphetamine than placebo. Shoptaw et al. (2008) also found that (56%) compared to placebo (40%), and lighter users also showed a greater rate of decrease methamphetamine at baseline, bupropion treatment increased weekly periods of abstinence Elkashef et al. (2008) showed that, for the subgroup of participants who had lighter use of studies. separate two from results by supported was users.view This heavy are who those than treatment in better do may presentation initial at ATS of quantities lower use who people that suggests experience Clinical users. ATS of subgroups particular benefit might Very little evidence is available concerning which medicines prescribed under what conditions Subgroups ofamphetamineusers studies totheAustralian clinicalsetting. international fromtranslating results in needed users.isCare methamphetamine injecting cent used ATS (Stafford & Burns, 2012), and studies from the United States rarely included different in the two countries. Among Australians who use drugs by injection, around 70 aresystems per treatment the and use methamphetamine of nature the because Australia for significant isThis States. United the in undertaken been have studies the of majority The Detailed findings 25 - Researchers suggest that a successful vaccine could be a highly effective adjunct to prevent to adjunct effective highly a be could vaccine successful a that suggest Researchers ing relapse to methamphetamine use if used in combination with supportive psychosocial therapy in long-term users, and as a treatment for methamphetamine overdose in acute (Gentry et al., 2009). medical settings in rats (Miller et al., 2012), which adds to the promising pool of results in these pre-clinical pre-clinical these in results of pool promising the to adds which 2012), al., et (Miller rats in of methamphetamine vaccines. trials (Moreno, Mayorov & Janda, 2011). One of & these (Moreno, immunoconjugates, Mayorov Janda, promising MH6, 2011). was and titres methamphetamine-antibody high produce again to found and re-tested recently concentrations methamphetamine brain lower and concentrations, blood methamphetamine did not reduce (Gentry et al., 2009), indicating that methamphetamine was still active in the central nervous system, which is undesirable following vaccination. high In in later result trials, six to found some with mice in tested were immunoconjugates methamphetamine bloodstream) the in molecules of (binding affinity high and titres methamphetamine-antibody To date, all trials of methamphetamine vaccines have been conducted in animal models. Early Early models. animal in conducted been have vaccines methamphetamine of trials all date, To anti-methamphetamine while that found rats in vaccines methamphetamine active of trials activity) locomotor (e.g. methamphetamine of effects behavioural increased, titres antibody allow natural clearance to occur Ruedi-Bettschen (Gentry, & 2009).Owens, Without anti effects system nervous central rewarding highly the barrier, brain blood the crossing bodies blocked. be of methamphetamine would also prompted a search for a vaccine for methamphetamine dependence. and Methamphetaminebloodstream the in molecules methamphetamine the sequester to designed are vaccines the target pathogen. Vaccines can be both active and passive in nature. Active vaccines introduce molecules that trigger the immune system to develop its own antibodies, while antibodies. pre-generated introduce vaccines passive results from Promising trials of vaccines for cocaine dependence (e.g. Martell et al., 2009) able for many Vaccines years. are designed to boost the body’s immune against response Vaccines for amphetamine dependence for amphetamine Vaccines no Phase II were or III identified, beenstudies but mootedThere of they for vaccines have with cocaine users. after successful trials users ATS for - many such and vaccines been common as polio, avail illnesses, measles Effective have for methamphetamine-dependent participants with comorbid opioid dependence compared compared dependence opioid comorbid with participants methamphetamine-dependent for solely on methamphetamine. to those dependent Comorbid disorders may also complicate clinical responses to medicines. Shearer et al. (2009) (2009) al. et Shearer medicines. to responses clinical complicate also may disorders Comorbid outcomes poorer and modafinil taking participants HIV-positive for outcomes poorer found Gender differences in outcomes were rarely reported in the studies reviewed. However, Elkashef Elkashef However, reviewed. studies the in reported rarely were outcomes in differences Gender in use methamphetamine reduced with associated was bupropion that showed (2008) al. et males but not in females. 26 Medication treatment options for amphetamine-type stimulant users Evidence ofbenefit rating legend:★★★Shows some benefit ★★Shows potential benefitbutcurrent evidence is limited★Shows littleor noevidenceofbenefit reduced? ATS use RCTs Number of effects Other omnsStudies Comments rating of benefit Evidence Key points studies Number of aeySafe Safety placebo than not more Yes, but 4 severity of to reduce Appears rate drop-out had ahigh ★ ★ ★ ★ ★ ★★ ★★★ ★★★ ★★★ ★★★ ★★★ 7 tolerated and well phetamine Dexam- but notuse dependence, severity of reducing benefits in Shows some dependence equivocal evidence Yes, but 2 rate drop-out had ahigh Studies 2 tolerated and well Safe hndt oaii Bupr Modafinil phenidate Methyl retention increasing potential in use and reducing benefits in some Shows slightly retention improve May medicine with compliant Yes, if 3 rate drop-out had ahigh Studies 5 tolerated and well Safe r benefits in some Shows retention treatment craving or effect on No compliant medication- use if educing more than Yes, butno 4 adherence medication had low Studies 4 tolerated and well Safe smoking tobacco reduces users, also with light effective more Is probably 30 days) days inlast users (<18 for lighter especially use, reducing benefits in some Shows lighter users among reductions placebo; but po Naltrexone opion 2 rate drop-out had ahigh Studies 3 tolerated and well Safe craving reduce retention, improve May craving and lower retention improve may use and reducing benefits some Shows equivocal evidence Yes, but Table 1.Overview ofstudiesreviewed forthetreatment ofamphetamine-typestimulantdependence 1 adherence medication had low Study 1 tolerated and well Safe Antidepressants with men have sex men who among reduced risk-taking Sexual of benefit indications Shows evidence but limited Possibly Mirtazapine in MSM risk-taking in sexual reduction some limited; is very but evidence 2 rate drop-out had ahigh Studies 2 events adverse increases Potentially events adverse and more retention Poorer use increase Appears to use increase May etaieFluoxetine Sertraline × 1 RCT Small pilot 1 tolerated and well Safe craving May reduce evidence but limited placebo than No more limited evidence is use, but but not craving, of reducing indications Shows ★★ 2 rate drop-out had ahigh Studies 3 Very high placebo less than study, but in one of use frequency Increased no effect use orhave increase May gabapentin and Flumazenil combination increase use and may protocol Complicated × events adverse rates of mild

1 rate drop-out a high Study had 1 severity of improve May limited evidence but Possibly tolerated and well Safe Anticonvulsants but evidence functioning general improve and may dependence severity of use and of reducing indications Shows ★ ★★ functioning general and dependence Topiramate is limited

1 rate drop-out a veryhigh Study had 1 oPossibly No tolerated and well Safe effectiveness potential evidence of Little orno retention craving or effect on No Gabapentin 0 study only Open-label 1 RCTs) limited (no evidence but defects visual field May cause gain in weight May result caution suggest deficits visual field serious over concerns limited, but Evidence is × Vigabatrin 0 Open-label 2 RCTs) limited (no evidence but Possibly tolerated and well Safe symptoms psy and memory verbal craving, ments in Improve- studies had limited evidence is but of benefit indications Shows ★★ out rate a high drop- studies only; Risperidone Antipsychotics chiatric × Shows evidence ofharm

2 2 no effect use orhave increase May effects unsafe side May have both events in adverse study and use inone Increased side effects adverse over concerns there are use and increase May reasons for safety abandoned had tobe One RCT × Aripiprazole 1 1 compliant medication when Reductions tolerated and well Safe its utility life limits short half- outcome, related to adherence Medication potential evidence of Little orno rate drop-out a high Study had Baclofen effectiveness ★ 1 1 oPossibly No tolerated and well Safe severity of craving or effect on No rate drop-out a high Study had Ondan setr ★ effectiveness potential evidence of Little orno dependence nVarenicline on io 1 1 pilot 1 limited evidence but reported Not underway is now scale trial A large- ★★ ★★ but evidence abstinence duration of retention and and increase reduce use, that itmay indications Shows abstinence duration of and retention improve May is limited

1 No reported Not only abstract study Single No Amlodipine effectiveness potential evidence of Little orno

27 Detailed findings Detailed 28 Medication treatment options for amphetamine-type stimulant users See summarytablebeginningonpage102 fordetails ofthis group ofstudies. amphetamine-type stimulantusers Treatment forco-occurringmentalhealthproblems among counter supplementintheUnited StatesbutnotinAustralia. over-the- an as available is which properties,neuroprotective have to thought compound occurring naturally a citicoline, using use drug in change no but symptoms,depressive in improvement found that trial randomised a was 2012) Gabrielson, & (Brown study One clinical practice. health mental problems among dependent amphetamine co-occurring users, making for it difficult to draw conclusionsmedication for examined that studies few very were There Richards, 2000;Sulaimanetal.,2012) were reviewed. & Oesterheld Kofoed, Misra, 1997; Kofoed, & Misra 2002; Holland, & Garvey Carnwath, and six case studies or open-label trials (Camacho, Ng & Frye, 2010; Camacho & Stein, 2002; A total of eight studies, two controlled trials (Brown & Gabrielson, 2012; Nejtek et al., 2008) Summary ofliterature reviewed amphetamine users with these disorders, under close supervision. Medicines to treat treat to Medicines supervision. close under disorders, these with users amphetamine for suitable also are population general the in disorders health mental for medicines that suggest available those studies, well-controlled of paucity a was there Although some positive effectsonbothpsychotic symptoms andamphetamineuse. risperidone and a combination of modafinil, quetiapine and divalproex appeared to have when using modafinil in those with pre-existing psychotic conditions. Dexamphetamine, caution advise (2009) al. et Shearer although studies, these in part taking participants Dexamphetamine and modafinil did not appear to exacerbate psychotic symptoms in the guidelines forgeneral populationprescribing underclosesupervision. are probably safe and may be effective for methamphetamine users if used within existing A range of medicines, including antipsychotics, dexamphetamine, modafinil and citicoline, health disorders co-occurring with amphetamine use because of the nature of the studies. It is difficult to draw any firm conclusions about the prescription of medicines for mental Overall summary amphetamines andfurtherresearch is needed. draw specific conclusions about the effectiveness of these medicines for people who use to difficult it makes measuresstandard of lack the with studies case of dominance The be required. using amphetamines but, given the lack of specific evidence, additional monitoring may mental health disorders in the general population are probably useful and safe for people Detailed findings 29 co-occurring mental health and ATS dependence are required. dependence are co-occurring mental health and ATS health disorders, and only two of the studies reviewed were controlled trials. All others were were others All trials. controlled were reviewed studies the of two only and disorders, health designs. single-case or sizes, sample small and group control no with trials open-label either Additional high-level studies of the efficacy and effectiveness of prescribed medicines for Research implications Research mental co-occurring and use amphetamine for medicines examining studies few were There similar to general studies of co-occurring drug use and mental health disorders, they appear appear they disorders, health mental and use drug co-occurring of studies general to similar safe for relatively use with this group and may be helpful in treating symptoms of mental review. to this of interest of amphetamine users among the cohort health problems showed ‘good’ or ‘some’ improvement in both drug use and mental health symptoms. in both drug use ‘good’ or ‘some’ improvement showed theseOverall, studies do not offer sufficient evidence on which to base recommendations However, problems. health mental co-occurring and use amphetamine of treatment the for ment therapy for amphetamine dependence, did not exacerbate psychotic symptoms among among symptoms psychotic exacerbate not did dependence, amphetamine for therapy ment patients eight the of Six schizophrenia. with users amphetamine dependent eight of group a to note, however, that Shearer et al. (2009) suggest caution when prescribing modafinil for modafinil prescribing when caution suggest (2009) al. et Shearer that however, note, to disorder thought of reports few the as disorders, psychotic or anxiety pre-existing with people unique to the modafinil group. study were found in that or anxiety symptoms - replace as prescribed dexamphetamine, that found 2002) al., et (Carnwath study case One depressive depressive symptoms and reduced craving for methamphetamine with no exacerbation of also was modafinil that found 2002) Stein, & (Camacho group same The symptoms. manic important is It dependence. amphetamine and phobia social of case single a treating in useful In a report of a single case, Camacho et al. (2010) concluded that a combination of modafinil, modafinil, of combination a that concluded (2010) al. et Camacho case, single a of report improved a In disorder affective bipolar with users methamphetamine for divalproex and quetiapine amphetamine users experiencing psychotic symptoms, including risperidone (Misra & Kofoed, Kofoed, & (Misra risperidone including symptoms, psychotic experiencing users amphetamine all of which (Sulaiman et al., 2012), et al., 2000) and aripiprazole 1997), olanzapine (Misra users. in amphetamine symptoms psychotic acute and residual in reducing effective were medicines improved manic and depressive symptoms and reduced cravings among this group. group. this among cravings reduced and symptoms depressive and manic improved medicines As no placebo control was employed, the most that can betreatment no than saidbetter are is they whether thatunclear is risperidoneit but effective, equally and are quetiapine for examined been have preparations antipsychotic other of number A treatments. other or A second randomised trial (Nejtek et al., 2008) compared risperidone and quetiapine, two antipsychotic medicines, for amphetamine use and bipolar and disorder showed that both 30 Medication treatment options for amphetamine-type stimulant users MDMA amphetamine (MDMA) use problems were identified and both were single-case designs. The Only two studies that examined the role of medicines for treating 3,4-methylenedioxymethyl Summary ofliterature reviewed on treating amphetamine dependence. focused if benefits health productivepublic more offer to likely ispharmacotherapies into Institute of Health and Welfare, 2012). Given the small numbers of dependent users,12 to compared concern, of researchdrug main a as ecstasy for of concern. In 2011–12, for example, there were 720 closed treatment(Degenhardt & episodesHall, 2010), across but Australiapresentation for treatment is relatively rare as a primary drug existssyndromepotentially dependence a that evidence thereissome settingsand clinical in dependence MDMA of reports few a areThereuse. heavy chronic with associated be to Most of the problems associated with MDMA involve acute toxicity and it is rare for MDMA Research implications three months treatment with mirtazapine. improvedfollowing useand attacks functioning panic decreasedself-reported patient The MDMA weekly; she had been abstinent for six years at the time of the study (Fetter, 2005). who reported depression and anxiety, which she linked to a period of one year when she used (Akhondzadeh & Hampa, 2005). The second study reported the case of 28-year-old woman taken was it when MDMA of effects subjective in reduction a and topiramate with ment four years, whoreported adramatic reduction inMDMAuse duringthree months oftreat- for week per times 28-year-old four a to of man two first case MDMA the using described more amenabletoharmreduction strategies. generally considered to be self-limiting over time. Most issues with MDMA are acute and lems,arethese unusual rarelyand isolationin from polydrug useMDMA dependence. is prob- long-term and dependence MDMA of reports been havethere although because, Research efforts are better directed towards treatment of methamphetamine dependence intervention remains thetreatment ofchoiceforthis group. exceptions of symptomatic relief from co-occurring mental health symptoms, psychosocial There is little evidence for the effectiveness of pharmacotherapy for MDMA and, with the value toclinicalsettings. little of studies case single both MDMA, for treatment of studies two only were There Overall summary 528 for amphetamines (Australianamphetamines for 528 Detailed findings 31 numbers of users, research efforts are likely to be better focused on treating methamphetamine methamphetamine treating on focused better be to likely are efforts research users, of numbers dependence. Only one study that examined the role of design. medicinessingle-case a was it for and review treating this in stimulantsidentified was MDMA and other methamphetamine than The study described the case of a 37-year-old woman with a history of major depression, for weight behaviour ephedrine who for had 20 used years and compulsive eating disorder weeks eight for aripiprazole plus fluoxetine with successfully treated was She management. after four months. and was ephedrine-abstinent the small Given among users. other than amphetamines become problematic few ATS Very Other amphetamine-type stimulants Other amphetamine-type 32 Medication treatment options for amphetamine-type stimulant users There is now a significant body of evidence for the effectiveness of psychological therapies ventions toofferpeoplewhouse ATS. opiate and alcohol-use disorders, coupled with a previous paucity of evidence-based inter- in part to the traditional focus of the alcohol and other drugs treatment sector on treating due be Thiscould 1999). al., et treatment(Vincent goalsareuntil met retaining them and Research suggests that services generally have difficulty attracting ATS users into treatment use ATS tend not to present for treatment until their problems are extreme physical(Baker and et psychologicalal., 2004).health problems, including neurotoxicity. Despite this, people who processes.significant Conversely,rangeof a severeinclude alsobe and adversecan effects usersand people intensereportispleasuremost feeling unrivalled that for by endogenous The acute effects of ATS in general, and methamphetamine in particular, are highly rewarding on theincrease sincedownturns were first reported in2004. Monitoring in Australia project (Sweeney & Payne, 2012) suggest that ATS use is once again 1998 (Australian Institute of Health and Welfare, 2011), and recent data from the Drug Use in use reported in spike significant a since market the dominated has Methamphetamine settings. treatment in clients among seen commonly not analogues other of handful a and MDMA as well as methamphetamine), and (amphetamine amphetamines include ATS years in accordance with availability, cost and cultural trends among people who use drugs. for decades and, like many drugs of abuse, their popularity has waxed and waned over the Australia in market drug illicit the on available been have stimulants Amphetamine-type Conclusions in Australia for this purpose and none can be recommended as a first-line treatment option. medicine in the treatment of ATS use disorders over another, thus no medicines areTo authoriseddate, there are insufficient data to demonstrate a universal benefit for any one particular services andhave dropped outoftreatment multipletimes. those who have been unsuccessful in maintaining engagement with psychosocial treatment multiple attempts at quitting or reducing ATS use on their own or under supervision, or for havehad who people those for important treatmentThisgainsisareparticularly as made. in concert with psychosocial interventions may help to retain people in care until such time earlier when evidence suggests they will benefit most. Secondly, offering pharmacotherapy several benefits. Firstly, have it maymay serve tomedicines attract moreeffective people to into treatment, access andusers attract ATS them dependent offering that possible is It supporting peoplewhoare dependentonATS is stillunclear. better in play pharmacotherapymight 2011),that role al., the et (Kennydate ment to but treat to barrier a as ATS for pharmacotherapy a of lack the identified have Practitioners people whodobeginpsychological therapy is high. among drop-out and it, from benefit would suggest estimates than treatment for present usersATS fewer this,substantially Despite 2008). Rawson, & (Lee services treatment drug and alcohol all in responses clinical guide to used be can which use ATS problematic for - Conclusions 33 the role of pharmacotherapy among people who are ATS-dependent, and to further identify identify further to and ATS-dependent, are who people among pharmacotherapy of role the prescribed. can be appropriately promise how best the medicines that show number of medicines that should be avoided because they have been shown to be harmful be to shown been have they because avoided be should that medicines of number users. with methamphetamine to use understand to still required is users, ATS among Australian particularly research, Additional with amphetamine users in the trials reviewed. in the trials users with amphetamine Given the likely widespread off-label prescribing of medicines for people dependent on methamphetamine (e.g. Dunlop et al., 2008), this discussion paper has also identified a and suitable for some people in some circumstances, particularly when pharmacotherapy within prescribed are and plan, treatment individualised and comprehensive a of part forms profile safety good a showed medicines these of Each framework. medicines of use quality a Findings from some of the 56 studies examined for this review suggest that some medicines medicines some that suggest review this for examined studies 56 the of some from Findings effective be may naltrexone) and methylphenidate modafinil, bupropion, (dexamphetamine, 34 Medication treatment options for amphetamine-type stimulant users Acapulco, Mexico,June 1999. at the61st AnnualScientificMeeting oftheCollegeonProblems ofDrugDependence, methamphetamine dependence —acontrolled trial:preliminary analysis. Paper presented Batki, S.L.,Moon,J.,Bradley, M.,Hersh, D.,Smolar, S.etal.(1999).Fluoxetine in Journal ofPsychiatryandNeuroscience, 31(5): 301–313. Lecomte, T. (2006).Theneedforspeed: anupdateonmethamphetamine addiction. Barr, A.M.,Panenka, W.J., MacEwan,G.W., Thornton,A.E.,Lang,D.J.,Honer, W.G. & and mechanisms ofaction.JournalClinicalPsychiatry , 67(4):554–566. Ballon, J.S.&Feifel, D.(2006).Asystematic review ofmodafinil:potentialclinical uses Addiction, 100(3): 367–378. behavioural interventions for regular amphetamineusers: astepintherightdirection. Baker, A.,Lee,N.K.,Claire, M.,Lewin,T.J., Grant, T. etal.(2005).Brief cognitive Canberra: Australian Government DepartmentofHealthandAgeing,pp.63–84. Psychostimulant Users. 2nded.(NationalDrugStrategy Monograph Seriesno.51.) In A.Baker, N.K.Lee&L.Jenner(eds),ModelsofInterventionandCare for Baker, A.,Gowing,L.,Lee,N.&Proudfoot, H.(2004).Psychosocial interventions. innervated brain regions. JournalofNeurochemistry, 66(2):443–448. cocaine treatment onmu-anddelta-opioidreceptor mRNAlevels indopaminergically Azaryan, A.V., Coughlin,L.J.,Buzas, B., Clock,B.J. &Cox, B.M. (1996).Effectofchronic alcohol-and-other-drug-treatment-services-data-cubes/>. (AODT–NMDS) datacubes. Retrieved 8February 2013, from . Commonwealth ofAustralia, 2012. Available from: Addictions methamphetamine abuse. of dexamphetamine The prescription & Holland, M. (2002). T. Garvey, Carnwath, T., amphetamine dependence. Journal of and to patients with schizophrenia Psychopharmacology, 16(4): 373–377. for the agonists & de Wit, H. (2002). GABA(B) receptor D.C. M.S., Roberts, Cousins, Drug and Alcohol Dependence, findings. of recent of drug addiction: a review treatment 65(3): 209–220. of the clinical pharmacology of K.R. (2009). A review C.C. & Dyer, Cruickshank, 1085–1099. methamphetamine. Addiction, 104(7): S. A., Blaszczyk, J., Tomkins, K.R., Quigley, C.C., Montebello, M.E., Dyer, Cruickshank, trial of mirtazapine for the management of & Shand, D. (2008). A placebo-controlled Drug and Alcohol Review, 27(3): 326–333. methamphetamine withdrawal. N.K. Lee & L. Jenner In A. Baker, Dean, A. (2004). Pharmacology of psychostimulants. . 2nd ed. (National Drug for Psychostimulant Users (eds), Models of Intervention and Care Department of Government Australian Canberra: Series no. 51.) Monograph Strategy Health and Ageing, pp. 35–50. 36 Medication treatment options for amphetamine-type stimulant users methamphetamine dependence.DrugandAlcohol Dependence,85(3):177–184. Randomized, placebo-controlled trial ofbaclofenandgabapentin forthetreatment of Heinzerling, K.G.,Shoptaw, S.,Peck, J.A.,Yang, X.,Liu,J.,Roll,J.&Ling, W. (2006). subject analysis. DrugandAlcoholDependence,63(3):269–276. treatment formethamphetamine dependence:aprospective, repeated-measures, within- Hartz, D.T., Frederick-Osborne, S.L.&Galloway, G.P. (2001). Craving predicts use during 1331–1345. use amonggayandbisexual meninNew York City. SubstanceUse&Misuse , 40(9–10): Halkitis, P.N., Fischgrund, B.N. &Parsons, J.T. (2005).Explanations formethamphetamine 1439–1464. pharmacotherapy forstimulantabuse anddependence.AddictiveBehaviors, 29(7): Grabowski, J.,Shearer, J.,Merrill, J.&Negus, S.S.(2004).Agonist-like, replacement 206–213. passive humanvaccines totreat methamphetamineaddiction.HumanVaccines, 5(4): Gentry, W.B., Ruedi-Bettschen,D.&Owens, S.M.(2009).Development ofactive and 276–282. treatment ofmethamphetamineaddiction.ClinicalPharmacology&Therapeutics, 89(2): A randomized, placebo-controlled trialofsustained-release dextroamphetamine for Galloway, G.P., Buscemi, R.,Coyle, J.R.,Flower, K.,Siegrist, J.D,etal.(2011). Addictions, 14(3):300–301. Fetter, J.C.(2005).MirtazepineforMDMA-induceddepression. AmericanJournalon 1162–1170. for thetreatment ofmethamphetaminedependence.Neuropsychopharmacology, 33(5): Elkashef, A.M.,Rawson, R.A.,Anderson, A.L.,Li,S-H.,Holmes, T. etal.(2008).Bupropion Addiction, 107(7): 1297–1306. treatment ofmethamphetamineaddiction:amulti-centerplacebo-controlled trial. Elkashef, A.,Kahn, R.,Yu, E.,Iturriaga,Li,S-H.etal.(2012). Topiramate forthe and Drug&AlcoholOffice. Evaluation oftheNSWStimulantTreatment Program. Sydney: NSWHealth,MentalHealth Dunlop, A.,Tulloch, B., McKetin, R.,Adam, T., Baker, A.&Wodak,(2008).Preliminary Turning Point AlcoholandDrugCentre. Withdrawal: aguideforpeopletryingtostopamphetamineuse.Rev. ed.Melbourne: Dunlop, A.,Hocking,S.,Lee,N.&Muhleisen, P. (2004).Gettingthrough Amphetamine conditioned placepreference. Synapse,63(2):87–94. gamma vinyl-GABA(R,S-GVG)blocks methamphetamine-triggered reinstatement of DeMarco, A.,Dalal,R.M.,Pai, J.,Aquilina, S.D.,Mullapudi,U.etal.(2009).Racemic Centre, University ofNewSouthWales. (MDMA) Use.(NDARCMonograph no.62.)Sydney: NationalDrugandAlcoholResearch Degenhardt, L.&Hall,W. (eds)(2010). TheHealthandPsychologicalEffectsof‘Ecstasy’ References 37 Herin, D.V., Rush, C.R. & Grabowski, J. (2010). Agonist-like pharmacotherapy for stimulant pharmacotherapy Agonist-like J. (2010). C.R. & Grabowski, Rush, Herin, D.V., Annals of the New York studies. and clinical human laboratory, dependence: preclinical, 76–100. , 1187(1): Academy of Sciences effects of modafinil The J. (2010). S. & Ferris, A., Nielsen, R., Lee, N., Pennay, Hester, bias performance during 7-day and attentional on neuropsychological treatment Experimental and Clinical methamphetamine dependence. from inpatient withdrawal , 18(6): 489–497. Psychopharmacology and psychostimulant H.L. (2008). Monoamine transporters Howell, L.L. & Kimmel, , 75(1): 196–217. addiction. Biochemical Pharmacology for all clinical conditions. Placebo interventions (2010). Gøtzsche, P.C. Hróbjartsson, A. & CD003974 [online]. , 2010(1): Database of Systematic Reviews Cochrane for the J. (2008). Naltrexone & Franck, A., Beck, O. N., Hammarberg, Jayaram-Lindström, trial. American placebo-controlled a randomized, of amphetamine dependence: treatment 1442–1448. Journal of Psychiatry, 165(11): In and detoxification. withdrawal (2004). Psychostimulant J.B. L. & Saunders, Jenner, Psychostimulant for N.K. Lee & L. Jenner (eds), Models of Intervention and Care A. Baker, Australian Canberra: Series no. 51.) Monograph . 2nd ed. (National Drug Strategy Users and Ageing, pp. 102–119. Department of Health Government N. (1997). Amineptine in the treatment & Jarusuraisin, M. Jittiwutikan, J., Srisurapanont, double-blind study. randomised, a placebo-controlled, of amphetamine withdrawal: , 80(9): 587–592. Journal of the Medical Association of Thailand of stimulant addiction. European for the treatment (2007). Ondansetron B.A. Johnson., Psychiatry, 22: 191. R. et al. (2008). Kahn, A.M., Smith, E.V., Ait-Daoud, N., Elkashef, B.A., Johnson, and study of the safety placebo-controlled double-blind, randomized, A preliminary of methamphetamine dependence. International in the treatment efficacy of ondansetron 1–14. , 11(1): Journal of Neuropsychopharmacology utilization and barriers Treatment A. (2011). A., Lee, N.K., & Pennay, Harney, P., Kenny, Substance Abuse of dependent methamphetamine users. of a survey results to treatment: , 6(1): 3. and Policy Prevention Treatment, & Mugavin, J. (2009). Alcohol and B. L., Hunter, L., Jenner, Swan, A. , Berends, P., Kenny, Alcohol and Drug Point guidelines. Melbourne: Turning practice Other Drug Withdrawal: Centre. D. & J., De Angelis, J., Copeland, L., Hickman, M., Macleod, J., McKenzie, Kimber, prospective in injecting drug users: and cessation Survival Robertson, J.R. (2010). study of outcomes and effect of opiate substitution treatment. observational c3172. BMJ, 341: 38 Medication treatment options for amphetamine-type stimulant users Abuse Treatment , 35(3):334–342. a comparison ofmirtazapine andmodafinilwithtreatment as usual. JournalofSubstance and sleep patterns duringinpatienttreatment ofmethamphetamine withdrawal: McGregor, C.,Srisurapanont, M.,Mitchell, A.,Wickes, W. &White,J.M.(2008).Symptoms media_library/conferences/hcpp/mcarthur.pdf>. Policing andPunishment Conference, Canberra, December1999:

participants 100 placebo fordays 1–5,and modafinil ormatching seven days (200 crushed incapsulesfor Modafinil orplacebo discharge) to titrate thedosebefore seven days (200 crushed incapsulesfor Modafinil orplacebo Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and discharge) to titrate thedosebefore 100 placebo fordays 1–5,and modafinil ormatching

mg fordays 6&7, mg fordays 6&7,

mg of mg of adverse events orsideeffectsreported. between groups onanyofthemeasures. There were no Due tolowpower, there were nosignificantdifferences Summary pressure, heartandrespiration rates. Questionnaire; andphysiological measures includedblood rated visual analoguescale,StMary’s Hospital Sleep Severity Assessment (ASSA);craving measured by participant- Symptoms Assessment (ACSA),AmphetamineSelective Withdrawal Questionnaire (AWQ),AmphetamineCessation in days; severity ofwithdrawal measured by Amphetamine A range ofclinicalmeasures including:retention intreatment Measures in attention-deficit hyperactivity disorder and schizophrenia. found inmore robustly powered studies ofcognitive benefits in executive functionandmemorywere consistent withthose significant, theeffectsizes of modafinil-related improvements significantly ameliorated by modafinil treatment. While non- treatment andrelapse potentialatfollow-upbutwasnot task. Themagnitude ofbiaspredicted bothretention in methamphetamine-related stimuliontheemotionalStroop All participantsshowed asignificantattentional biasfor learning, visual memory, processing speed, orverbal fluency. memory tasks. Nobenefitwas seenformeasures of verbal toward improvement onexecutive functionanddelayed immediate verbal memoryrecall anda non-significant trend Treatment wasassociatedwithasignificant improvement in Summary Stroop test, methamphetamine word emotional Stroop trolled Oral Word Association test (COWAT), Trail Making test, — Digit–Symbol Substitution test); executive function (Con- (RCFT)); working memory (Digit Span test, Psychomotor speed Verbal Learning test (RAVLT) and Rey Complex Figure test Adult Reading Test); verbal and visual memory (Rey Auditory Neuropsychological test battery including: literacy (National Measures

t ask). RCT (pilot) controlled placebo- double-blind Level II— vdneQualityassessment evidence Level of RCT (pilot) controlled placebo- double-blind Level II— Hester etal.(2010). Same datasetas McKetin et al. (2012). treatment reported by amphetamine users in a large cohort of meth- slightly less severe than, This is similar to, but and were all injectors. six years on average using for more than users but had been Cohort were not daily sample size. study, butsmall Well-conducted pilot study. testing. Inpatient neuropsychological low follow-upfor sample sizeand study, butsmall Well-conducted pilot

49 Appendix: Summary tables Summary Appendix: 50 Medication treatment options for amphetamine-type stimulant users Reference America United Statesof CD003021. Reviews, 2009(2): of Systematic Cochrane Database withdrawal. for amphetamine (2009). Treatment Shoptaw, S.J.etal. Australia 35(3): 334–342. Abuse Treatment, Journal ofSubstance treatment asusual. modafinil with mirtazapine and comparison of withdrawal: a methamphetamine treatment of during inpatient and sleep patterns (2008). Symptoms McGregor, C.etal. modafinil Mirtazapine, Medicine mirtazapine Amineptine, (n=22) received treatment asusual (TAU) comparison group whohad or modafinil(n=14).Ahistorical Randomised tomirtazapine(n=13) % injectors: notreported Mean use inlastmonth:23.6days use: 10 years Mean years ofmethamphetamine Mean age:31.3 years Males n=27(55%) users (inpatients) 49 dependentmethamphetamine of Number anddescription participants controlled trials involving 125 A review offourrandomised

participants was administered forpain) and non-opioidanalgesia (2.5–10 treatment asusual (TAU) necessary (PRN)whichwas pericyazine asper group receiving a historical comparison days) were compared to (60 day) andmirtazapine Modafinil (400 (10–20 (5–10 either nitrazepam (5–10 all groups (diazepam were available PRNfor Symptomatic medications oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and compared toplacebo and twoofmirtazapine Two studiesofamineptine

mg/day forupto10

mg) ortemazepam mg) foranxiety,

mg) forinsomnia, mg/day)

mg/ in comparison tomirtazapine. had amilderwithdrawal syndrome andlesssleep disturbance to TAU-treated participants;modafinil-treated participants participants showed milderwithdrawal symptoms compared and transient. Bothmodafinil-andmirtazapine-treated effects inthis open-labelstudy. Sideeffectswere mild minimal positive subjective effectsandnodiscontinuation Modafinil andmirtazapinewere welltolerated, producing Summary Questionnaire. Scale; BeckDepression Inventory II;StMary’s Hospital Sleep Symptoms Assessment (ACSA);ClinicalGlobalImpression Severity ofDependenceScale;AmphetamineCessation Measures amphetamine withdrawal symptoms. any benefitofmirtazapine over placebo on retention oron amphetamine withdrawal. Amore recent studyfailedtofind reduce hyperarousal andanxietysymptoms associatedwith were notasclear. Onestudysuggestedthatmirtazapinemay over placeboforreducing amphetamine withdrawal symptoms craving compared toplacebo.Thebenefits ofmirtazapine presentation, butdidnotreduce withdrawal symptoms or discontinuation rates andimproved overall clinical Two studiesfoundthatamineptinesignificantly reduced Summary trial (pilot) randomised double-blind Level II— vdneQualityassessment evidence Level of review systematic Level I— et al.(2012). reported by McKetin users intreatment methamphetamine to alarge cohortof average. This is similar using for10 years on users andhadbeen Cohort were neardaily placebo control. small sample size.No Pilot open-labelstudy, review. High-quality Cochrane

51 Appendix: Summary tables Summary Appendix: 52 Medication treatment options for amphetamine-type stimulant users Thailand 20(5): 253–256. Psychopharmacology Reference International Clinical pilot study. placebo-controlled detoxification: a in amphetamine (2005). Mirtazapine Kongsakon, R.etal. Australia 27(3): 326–333. and AlcoholReview, withdrawal. Drug methamphetamine management of mirtazapine forthe controlled trialof A placebo- et al.(2008). Cruickshank, C.C. , itzpn 20dependent methamphetamine Mirtazapine Medicine itzpn 31 dependentmethamphetamine Mirtazapine or placebo(n=11) Randomised tomirtazapine(n=9) % injectors: notreported reported Mean use inlastmonthnot use notreported Mean years ofmethamphetamine Mean age:24.3years Males n=20(100%) (inpatients) users inaprobation centre of Number anddescription (n=13) orplacebo(n=18) Randomised toreceive mirtazapine % injectors: 54.8% Mean use inlastmonth:22.4days use: notreported Mean years ofmethamphetamine Mean age:31 years Males n=19(63%) other drugs significant risk ofwithdrawal from prior torecruitment andnotat methamphetamine inthe72hours users (outpatients)whohadused

participants groups narrative therapy both + five sessions of45mins administered unsupervised, Mirtazapine 15–60 Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and initiation oftreatment. up ondays 3&14after Participants were followed response over 14days. the participants’clinical and titrated according to an initialdoseof15 per dayorplacebowith Mirtazapine 15 Medications were self- a further12nights. mirtazapine noctefor two nightsand30 placebo onthefirst

mg or

mg mg

mg measures. Adverse events notreported. No significantdifferences betweengroups onanyofthe Summary Drug Use subscale. Severity ofDependenceScale;OpiateTreatment Index(OTI) subscale BSI–GSI;Depression–Anxiety–Stress Scale(DASS); Athens Insomnia Scale(AIS–5);BriefSymptomInventory (BSI) Amphetamine Cessation Symptoms Assessment (ACSA); A range ofclinicalmeasures including:Treatment retention; Measures in depression scores withinorbetween the groups. anxiety atdays 3and14.Nosignificantdifferences were seen in favour ofmirtazapinewere also seeninhyperarousal and score changesatdays 3and14.Significant improvements differences betweenthetwotreatment groups intotalAWQ nausea andvomiting, were reported. There were significant 30 mg/day. Mildadverse events, suchasheadache,sedation, dose of15mg/dayandvery fewrequired ahigherdoseof Most participantsresponded welltomirtazapineontheinitial Summary Questionnaire (AWQ). symptoms measured by theAmphetamineWithdrawal Depression rating scale(MADRS)andATS withdrawal Depression wasmeasured using theMontgomery–Asberg Measures RCT (pilot) double-blind Level II— vdneQualityassessment evidence Level of trial (pilot) controlled placebo- Level II

— psychotherapy. effects ofadded to assessanyceiling week study).Difficult completed thefive- phase and32% two-week medication (52% completedthe and highdrop-out small sample size pilot study, but Well-conducted was doubleblinded. unclear whetherstudy Small sample size,

53 Appendix: Summary tables Summary Appendix: 54 Medication treatment options for amphetamine-type stimulant users Reference Srisurapanont, Thailand 94–98. Psychiatry, 33(1): Zealand Journalof Australian andNew treatment. of amineptine double-blind study randomised, placebo-controlled, withdrawal: II.A Amphetamine et al.(1999). Thailand 2001(4): CD003021. Systematic Reviews Database of withdrawal. for amphetamine al. (2001). Treatment Srisurapanont, M. et Thailand 587–592. Thailand, 80(9): Association of of theMedical blind study. Journal randomised, double- placebo-controlled, withdrawal: a of amphetamine in thetreatment (1997). Amineptine Jittiwutikan, J.etal. Cochrane

M. , Medicine mnpie44methamphetamine-dependent Amineptine mnpieAreview oftworandomised Amineptine mnpie30dependentoral amphetamine- Amineptine of Number anddescription or placebo(n=22) Randomised toamineptine(n=22) % injectors: notreported 23.5 months Mean amphetamine-use duration: reported Mean use inlastmonth:not use: 2years Mean years ofmethamphetamine Mean age:19years Males n=41 (93%) inpatients participants controlled trials involving 74 n=15 orplacebo Randomised toeither amineptine % injectors: notreported Mean months ofuse: 23.6 Mean age:18.5years Males n=29(97%) amphetamine withdrawal using inpatients, withDSM–IV

participants oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and necessary foranxiety) day for5–14days asper lorazepam 0.5–1.5 daily for14days (plus Amineptine 300 compared toplacebo Two studiesofamineptine placebo for14days five days andmatching day titrated over thefirst Amineptine 300

mg mg/

mg/ (6/22), thoserates were notsignificantlydifferent. group (1/21) wasmuchlowerthanthatofplacebogroup rate duetodissatisfaction withtreatment intheamineptine the placebogroup atweek2.Althoughthediscontinuation significantly lowerfortheamineptinegroup thanforthoseof score, orCGIscore attheendofweek1.Total CGIscore was AWQ hyperarousal score, AWQanxietyscore andAWQtotal significant differences were foundonanycomparisons of lower thanthoseoftheplacebogroup atweeks 1and2.No vegetative scores oftheamineptinegroup were significantly score ateitherweek1or2.ButmeanAWQreversed No differences were observed betweengroups onAWQtotal Summary Global Impression (CGI)Scale. Amphetamine Withdrawal Questionnaire (AWQ);Clinical Measures came from onlyonestudyeach. results onamphetaminewithdrawal symptoms andcraving of amineptineonamphetaminewithdrawal symptoms. The and globalstate,asmeasured by CGI,butnodirect benefit Both studiesshowed somebenefitsfordiscontinuation rate Summary which is atrend butnotsignificant. so forlackofefficacy—n=1 amineptineandn=5placebo— compared toplacebo. Sixoftheeightwhodropped outdid clinical presentation, buthadnoeffectoncraving when Amineptine improved self-reported depression andoverall Summary treatment (ClinicalGlobalImpression scale —CGI). depressed mood,noenergy andfeeling sick);andeffectsof (a visual analoguescalemeasuringfourdomains ofcraving, Cocaine Craving andRelatedResponses (QECCRR);craving Stimulant withdrawal symptoms: Questionnaire forEvaluating Measures vdneQualityassessment evidence Level of trial (pilot) controlled placebo- double-blind Level II— review systematic Level I— trial randomised controlled placebo- double-blind Level II— histories ofATS use. users withlonger generalisable toolder results maynotbe of ATS use, so less thantwoyears nearly allmenwith Cohort wasyoung; size. RCT withsmall sample Well-conducted pilot reported. review, butminimally High-quality Cochrane amphetamine. term, heavierusers of findings tolonger- limits generalising than twoyears which been using forless all menandhad were young, nearly oral amphetamine, All participantsused small RCT. Well-conducted but

55 Appendix: Summary tables Summary Appendix: 56 Medication treatment options for amphetamine-type stimulant users America United Statesof 276–282. Therapeutics Pharmacology & addiction. methamphetamine for treatment of dextroamphetamine sustained-release controlled trial of randomized, placebo- et al. (2011). A Galloway, G.P. Reference Australia 146–154. Addiction, 105(1): dependence. methamphetamine the treatment of maintenance for dexamphetamine controlled trialof (2010). Randomized Longo, M.etal. Clinical , 89(2): (d-AMP) phetamine Dexam- Medicine phetamine Dexam- (n=30) ord-AMP Randomised toeitherplacebo group smoked MAprimarily) active group and67%placebo % injectors: notreported (80% 16 days Mean use inlastmonth:approx. Mean years ofuse: 2years Mean age:37years Males n=34(57%) users (outpatients) 60 dependentmethamphetamine of Number anddescription (n=26) dexamphetamine (n=23) orplacebo Randomised toreceive either % injectors: 86% days Median use inpast3months: 69 years Mean agefirst use: approx. 20 reported Mean use inlastmonth:not use: notreported Mean years ofmethamphetamine Mean age:31.9 years Males n=24(61%) IV previous 12months. 86%were more days perweekover the methamphetamine onthree or using outpatientswhohadused 49 dependentmethamphetamine-

users. participants week fornineweeks. therapy sessions oncea motivational enhancement manual-based individual All received 50-min. on subsequentdays. two equallydivideddoses on thefirst dayandas was given asasingledose daily foreightweeks. This release (SR)orplacebo 60 Primaryoutcomesincludingmeasures used Participants received either comparison ifrelevant Intervention and initial doseof20 up to14days, withan stabilisation periodof comprised aninitial The studyperiod amphetamine users. therapy (CBT) for of cognitive behaviour received four sessions Plus allparticipants capsules. numbers ofplacebo receiving increasing with theplacebogroup assessed by AWQ), stabilisation (withdrawal participants underwent day for90days. All a maximumof110 stabilised orinreceipt of daily asrequired until increased by 10 of dexamphetamine day ofaSRformulation

mg d-AMPsustained-

mg/

mg/ events. occurred duringthetrial,butn=30reported mildadverse and fewerwithdrawal symptoms. Noserious adverse events The dexamphetamine group reported significantlylesscraving Summary self-report. (visual analoguecraving scale);medicationadherence Questionnaire (AWQ);TheDesire forSpeedQuestionnaire (Time LineFollow Back—TLFB);AmphetamineWithdrawal (collected twiceweekly);self-reported methamphetamineuse Number ofmethamphetamine-negative urinedrugscreens Measures group. symptom severity duringstabilisation inthedexamphetamine a trend toward greater reduction ofreduced withdrawal pharmacist-supervised, dailydosingconditions. There was Dexamphetamine waswelltolerated andsafe under Summary Dependence Questionnaire —LDQ);treatment retention. and follow-up);degree ofdependenceover time(Leeds at three time-points(baseline,theendofmaintenance, Self-reported methamphetamineuse andhairanalysis Measures RCT controlled placebo- multi-site double-blind Qualityassessment Level II— evidence Level of RCT controlled placebo- double-blind, Level II— of twoyears. using foranaverage users andhadbeen Cohort were notdaily users. methamphetamine in dependent measures withdrawal for dependencebut to examine treatment originally designed double-blind RCT, Well-conducted beginning ofthetrial. been using atthe the participantshad methamphetamine or howmuch Unclear howlong the placebogroup. from thetrialamong high rate ofattrition Small sample sizeand symptoms. measured withdrawal dependence butalso methamphetamine dexamphetamine for designed toexamine blind RCT, originally Australian double- Well-conducted,

57 Appendix: Summary tables Summary Appendix: 58 Medication treatment options for amphetamine-type stimulant users Dexamphetamine andother psychostimulants Treatment foramphetaminedependence America United Statesof 89(2): 276–282. & Therapeutics, Pharmacology addiction. Clinical methamphetamine for treatment of dextroamphetamine Medicine Reference sustained-release controlled trialof placebo- A randomized, et al.(2011). Galloway, G.P.

phetamine Dexam- mine use inlast30 Mean 18.9days ofmethampheta- Mean age:37years Males n=15(50%) users 60 dependentmethamphetamine (n=30) orplacebo Randomised todextroamphetamine of Number anddescription

participants

days if Intervention andcomparison once aweekfornineweeks. enhancement therapy sessions based, individualmotivational All received 50-min.,manual- subsequent days. as twoequallydivideddoseson single doseonthefirst dayand eight weeks. This wasgiven asa d-AMP SRorplacebodailyfor Participants received either60

relevant

mg Primary outcomesincludingmeasures used dispensed medication. treatment sessions. Around 75%ofbothgroups tookthe on medicationadherence orattendanceatpsychosocial trial. There wasnosignificantdifference betweengroups symptoms. Noserious adverse events occurred during the reported significantlylesscraving andfewerwithdrawal free urinesamples), butthedextroamphetamine group methamphetamine using days, numberofmethamphetamine- on methamphetamineuse measures (self-reported There were nosignificantdifferences betweengroups Summary scale); andmedicationadherence self-report. The (TLFB); AmphetamineWithdrawal Questionnaire (AWQ); Secondary measures: self-reported methamphetamineuse urine drugscreens (collectedtwiceweekly). Primary measure: Numberofmethamphetamine-negative Measures

Desire forSpeedQuestionnaire (visual analoguecraving RCT controlled placebo- multi-site double-blind evidence Level of Level

— follow-up rate. low lossto adherence and medication size, reasonable sufficient sample RCT witha Well-conducted assessment Quality

59 Appendix: Summary tables Summary Appendix: 60 Medication treatment options for amphetamine-type stimulant users Australia 146–154. Addiction, 105(1): dependence. methamphetamine Medicine Reference United Kingdom 11(3): 205–216. Substance Use, audit. Journalof retrospective a 10-year pregnancy: prescribing in substitute Dexamphetamine al. (2006). White, R.et the treatment of maintenance for dexamphetamine controlled trialof Randomized et al.(2010). Longo, M. phetamine Dexam- phetamine Dexam- (n=26) dexamphetamine (n=23)orplacebo Randomised toreceive either 69 Median use inpast3months: Mean age first use: approx. 20 years reported Mean use inlastmonth:not use: notreported Mean years ofmethamphetamine Mean age:31.9 years Males n=24(61%) 86% were IVusers week over theprevious 12months. mine onthree ormore days per users whohadused methampheta- 40 dependentmethamphetamine of Number anddescription reported Mean use inlast30 days: not use: notreported Mean years ofmethamphetamine Injecting use: 56.8% Mean age:26.7years Females only population users andmembers ofthegeneral two equivalent groups ofheroin not amphetamine-using, and phetamine, 41 womenwhowere who were prescribed dexam- 47 amphetamine-using women

participants days used on anoccasionalbasis. choice, butdihydrocodeine is also methadone asthetreatment of Pregnant heroin users are offered before the third trimester. Thus, ideally, patients are detoxified than for a woman on methadone. can usually be done at a faster rate nancy and an expectation that this dexamphetamine through the preg- emphasis on reducing the dose of amphetamine users. There was an and 60 tered elixir being between 30 typical doses of an orally adminis- Dexamphetamine substitution, with users. sessions ofCBT foramphetamine Plus allparticipantsreceived four completing treatment. followed uptwomonths after experienced. Participants were any withdrawal symptoms month inorder tominimise off themedicationover one period, participantswere tapered At theendofmaintenance numbers of placebo capsules. placebo group receiving increasing drawal assessed by AWQ), with the underwent stabilisation (with- day for 90 days. All participants receipt of a maximum of 110 lised or until the participant was in 10 of dexamphetamine increased by 20 to 14 days, with an initial dose of initial stabilisation period of up The study period comprised an if Intervention andcomparison

relevant

m m g daily as required until stabi- g/day of a SR formulation

m g, is offered to pregnant

m m g g/ attended atleastoneCBT session(NS). in thedexamphetamine group and54%intheplacebogroup than thoseintheplacebogroup (n=18/26)(P=0.040);61% significantly lesslikelytodrop outofthestudy(n=8/23) during stabilisation. Thoseondexamphetamine were degree ofdependenceandwithdrawal symptomseverity Dexamphetamine increased treatment retention, reduced (86.3 days) compared toplacebo(48.6days). dexamphetamine stayed intreatment significantlylonger to treat (ITT)analysis showed thatparticipantstaking pharmacist-supervised, dailydosingconditions. Intention Dexamphetamine waswelltolerated andsafe under Summary Dependence Questionnaire); treatment retention. and follow-up);degree ofdependenceover time(Leeds at three time-points(baseline,theendofmaintenance, Self-reported methamphetamineuse andhairanalysis Measures continued use ofstreet-drugs. be informedofpossiblerisks, includingthoserelating to caution andused as alast-linetreatment. Clientsshould that dexamphetamine substitutionshould beinitiatedwith predictor ofadverse birthoutcomes. Theauthors concluded prescribing ormaximum dose.‘On-top’use wasthebest There wasnoassociationdemonstrated withduration of were very similarinthosenotprescribed dexamphetamine. related toprescribed dexamphetamine, asbirthweights groups, whichwasnotconsidered tobesubstantially There wasahighrate oflowbirth-weight babiesinboth Summary and druguse. Cigarette andalcoholuse, outcomeby prescription regime Measures Primary outcomesincludingmeasures used RCT controlled placebo- double-blind, Level controls historical cohort with retrospective using data analysis secondary Level IV— evidence Level of

— symptoms. withdrawal but also mine dependence methampheta- phetamine for examine dexam- designed to Originally placebo group. trial amongthe attrition from the and highrate of Small sample size double-blind RCT. Australian A well-conducted, randomised. and not was opportunistic comparison group control or reliable. The considered other datawere missing, although some datawere records and keeping ofclinical relied onrecord cohort studybut retrospective Well-analysed assessment Quality measur ed

61 Appendix: Summary tables Summary Appendix: 62 Medication treatment options for amphetamine-type stimulant users eeec Medicine Reference United Kingdom 94–97. 12(Suppl. and Policy, Prevention Drugs: Education, controlled trial. randomised a two-centre dependence: amphetamine a treatment of substitution as Dexamphetamine al. (2005). Merrill, J.et Australia 1289–1296. Addiction, 96(9): dependence. amphetamine substitution for dexamphetamine study of controlled randomized al. (2001). Pilot Shearer, J.et

1): phetamine Dexam- phetamine Dexam- of Number anddescription Mean use inlast7days: 19.3 use: notreported Mean years ofmethamphetamine Mean age:notreported Males n=42(71%) 56% injectors 59 dependentamphetamineusers, alone (BATA) n=27 n=32 orbestavailable treatment Randomised todexamphetamine only n=20 counselling n=21 orcounselling Randomised todex. plus month priortointake 31% shared injectingequipmentin use: 10 years Mean years ofmethamphetamine Mean age:29years Males n=24(83%) 95% injectingdrugusers 32% homosexualorbisexual men; 41 dependentamphetamineusers;

participants

g if Intervention andcomparison period). months (endofdex.prescribing then fortnightlyuntilseven appointments forfourweeks, received weeklyclinical After randomisation, participants clinically indicated. for inpatientdetoxification if and insomnia; andthepossibility prescribing fordepression, anxiety other supports;symptomatic minimisation advice;referral for advice onhealthylifestyles;harm coping andlapsemanagement; drug use diary;discussion ofcues, motivational interviewing(MI); literature onamphetamines; BATA consisted ofproviding treatment (BATA), orBATA alone. three months) plus bestavailable for fourmonths, thentaperfor by apharmacist (maintenance 100 dexamphetamine tabletsupto Random assignmentto week 12. to amaximumdoseof40 reduced inthefinal twoweeks dose wasachieved. Thedosewas 5 began at20 oral doseof60 to amaximumdailysupervised were prescribed dexamphetamine addition, thetreatment group psychological counselling. In All participantsreceived

mg dailyuntilamaximum relevant

mg perdaydispensed daily

mg, increasing by

mg. Induction

mg at Primary outcomesincludingmeasures used dexamphetamine group onphysical healthindicators. in psychological healthandsignificantimprovement inthe toward thereduction ofpolydrug use andimprovements difference ininjectingbehaviourbetweenthegroups. Atrend measures withbothgroups reporting reductions andno There wasnosignificantdifference betweengroups on use Summary measure specified). offending behaviour, andsatisfaction withtreatment (no psychological health,socialfunctioningandqualityoflife, Standard questionnaires ondruguse, physical and Measures There were noreports ofadverse events. compared withcontrols atpost-treatment butnot follow-up. reduced significantly more amongtheactive treatment group groups inamphetamine use. Theseverity ofdependence counselling. There wasnosignificantdifference between Treatment participantswere significantly more likelytoattend amphetamine dependencewere observed inbothgroups. Non-significant reductions instreet amphetamine use and Summary Dependence Scale(SDS). amphetamine use (OpiateTreatment Index—OTI); Severity of Urine screens atbaseline,6weeks and12weeks; self-reported Measures RCT (pilot) double-blind evidence Level of reported Blinding not Level IIRCT. Level II— were included. or bisexual men proportion ofgay relatively large adherence. A low medication drop-out and size andhigh small sample study witha Well-conducted assessment Quality control. and noplacebo Small sample size lacked detail. was briefand trial butreporting A well-designed

63 Appendix: Summary tables Summary Appendix: 64 Medication treatment options for amphetamine-type stimulant users eeec Medicine Reference United Kingdom 229–238. Addiction, 95(2): investigation. abuse: aninitial of amphetamine the treatment substitution in Dexamphetamine White, R.(2000). United Kingdom 52(1): 79–84. Dependence, Drug andAlcohol comparison. methadone: a or oral dexamphetamine prescribed oral among clients drug misuse of intravenous (1998). Levels & Griffiths, V. Charnaud, B. phetamine Dexam- phetamine Dexam- of Number anddescription obtained for148users. longitudinal outcomedatawere socio-demographic dataand retrospectively andcross-sectional prescriptions were examined users receiving dexamphetamine The standardised records of220 dexamphetamine elixir (n=60) Either onmethadone(n=120) or reported Mean use inlast30days: not group) injecting heroin formethadone methamphetamine: 7years (9 Median years ofinjecting methadone group) dexamphetamine (32years Mean age:28years (methadone) (dexamphetamine), n=98(82%) Males n=52(87%) replacement pharmacotherapy least sixmonths priortoreceiving amphetamine on a daily basis for at UK whowere injectingheroin or drug treatment serviceinthe 180 clientsofacommunity

participants

years if Intervention andcomparison counted. Injection siteswere routinely continued untilstreet-use ceased. of 90 of levels ofuse uptoamaximum dosing wasbasedonself-reports exclusively inelixirform.Initial Dexamphetamine wasprescribed at 1 negotiated withclients) methadone of44 (range 15–75 amphetamine sample was43 dose ofdexamphetamine forthe dexamphetamine elixir—mean street amphetamineto20 Dose usually calculatedas1

relevant

mg permlelixir(dex.dose

mg. Theprescription was

ml) vsmeandoseof

ml (11–80

g ml),

ml Primary outcomesincludingmeasures used injecting users. Relapse occurred laterwithamedianof16.0months for oral users relapsed intostreet-use aftersuccessfullystopping. in treatment. 13.6%(n=13)ofinjectors and9.4%(n=5)of a slower changeindrug-use behaviours, butalongerperiod although forbothgroups beingfemalewasassociatedwith a goodoutcomediffered betweenoral andintravenous users, was related toshorter timeintreatment. Variables predicting months ofcomingintotreatment. Failure tostopinjecting injectors stoppedinjecting,more thanone-third withintwo users makingmore overall gains intreatment. Over halfthe Oral andinjectingusers hadsimilaroutcomes, withinjecting Summary Ceasing illicituse; treatment retention. Measures on methadone. dexamphetamine maintenancedidjust as wellheroin users time intreatment, suggestingthatamphetamine users on between thegroups, includinginjecting rates, median of treatment. There were nodifferences inoutcomes There were nodifferences betweengroups atthebeginning Summary injection sites). of injectingatdischarge (assessedby visual observation of of use, duration oftreatment, psychotic episodes, andlevel Demographic characteristics, ageoffirst drug use, duration Measures (1995–96) years over two evidence Level of cohort retrospective using data analysis secondary Level IV— chart review retrospective Level

— application. with real world measures, but outcome not standardised, using clinical, chart review retrospective but low-level A well-conducted assessment Quality cohort study. retrospective low-level Well-analysed,

65 Appendix: Summary tables Summary Appendix: 66 Medication treatment options for amphetamine-type stimulant users Finland New Zealandand 1279–1286. Addiction, 108(7): controlled trial. blind, placebo double- a randomised, dependence: methamphetamine Medicine Reference Finland 164(1): 160–162. of Psychiatry, American Journal dependence. amphetamine and placebofor methylphenidate, aripiprazole, comparison of al. (2007).A Tiihonen, J.et amphetamine/ for treatment of methylphenidate Extended release et al.(2013). Miles, S.W. phenidate methyl Aripiprazole, Methyl phenidate 53 dependentamphetamineu (n=17) methylphenidate (n=17)orplacebo Randomised toaripiprazole (n=19), use: approx. 14years Mean years ofmethamphetamine Mean age:32.2years Males n=36(68%) placebo) methylphenidate group and10 for at baseline(mean10.5 for severity ofdependence(SDS) Participants hadhighscores on n=40 orplacebon=38 Randomised tomethylphenidate screens atbaseline methamphetamine-positive urine All participantsreturned use: 21.5 years Mean years ofmethamphetamine 35.3 years forNewZealand Mean age:37.5years forFinland; Males n=48(61%) amphetamine) from Finland(mainlyinjectors of of methamphetamine)andn=38 from NewZealand(mainlysmokers methamphetamine u 79 dependentamphetamine/ of Number anddescription

participants sers n=41 sers second week,and54 Equivalent gelcapsuleplacebo thereafter the first week,36 Methylphenidate 18 Aripiprazole 15 equivalent) 18 Methylphenidate (oraplacebo if Intervention andcomparison dosing. attended theclinicsdailyfor the 22-weektrial.Participants for 20weeks untiltheendof second week,and54 first week,36

relevant

mg dailyforthe

mg/day

mg/day forthe

mg/day for

mg/day mg daily reported aripiprazole significantlyworsened symptoms. placebo group. Thetrialwasceasedafterinitial analysis fewer amphetamine-positive urinesamples thandidthe group. Thosewhoreceived methylphenidate hadsignificantly amphetamine-positive urinesamples than didtheplacebo Patients allocatedtoaripiprazole hadsignificantlymore Summary treatment. amphetamine-positive urinesamples during pharmacological The primaryoutcomemeasure wastheproportion of Measures Primary outcomesincludingmeasures used for dailyclinicvisits fordosing. suggest highattritioncouldbedueinparttotherequirement placebo) butneitherreached statistical significance.Authors craving scores (–21.2 formethylphenidatevs–13.3 scores (–3.7formethylphenidatevs–1.6placebo)and methylphenidate group. There wasadecrease inmeanSDS group havingasignificantlylower retention rate thanthe study —only34.2%completed22weeks, withtheplacebo scale orSDS.There wasahighattritionrate from the returned by participantsordecreasing scores onthecraving reducing thenumberofmethamphetamine-positive urines Methylphenidate wasnomore effective thanplaceboin Summary Identification Test —AUDIT);andadverse medicationeffects. (visual analoguescale);alcoholuse (AlcoholUse Disorders of DependenceScale(SDS);methamphetaminecraving current substanceuse (Pompidou questionnaire); Severity Urine drugscreens formethamphetamine;previous and Measures trial randomised controlled placebo- double-blind RCT controlled placebo- Double-blind Level II— evidence Level of for analysis. of missing data high proportion sample sizeand analysis butsmall study withITT A well-conducted rate. by highattrition Findings limited conducted trial. well-designed and High-quality, assessment Quality

67 Appendix: Summary tables Summary Appendix: 68 Medication treatment options for amphetamine-type stimulant users Modafinil America United Statesof 135–141. 120(1–3): Dependence, Drug andAlcohol dependence. methamphetamine the treatment of Modafinil for Medicine et al.(2012). Anderson, A.L. Reference oaii 210 dependent Modafinil placebo (n=68) 400 mgdaily(n=70),or mg daily(n=72),modafinil Randomised tomodafinil200 reported methamphetamine use: not Mean years of 30 n=125(59.8%) methamphetamine use inpast >18 days of Mean age:39years Males n=124(59%) methamphetamine users of Number anddescription

participants day, or 200 12 weeks ofmedication:modafinil if Intervention andcomparison week 3. of motivational enhancementat All participants received one session week for12weeks. group counselling three timesper standardised 90-minutesofCBT All participantsreceived

relevant

mg/day, modafinil 400

placebo

mg/ Global Impression Scale (CGI); HIV Risk-Taking Behaviour Scale. Scale (HAM–D); adverse events; Brief Substance Craving Scale; Clinical treatment; Addiction Severity Index (ASI); Hamilton Depression Rating methamphetamine metabolites; abstinence at termination of Methamphetamine non-use weeks assessed by urine samples for period, nonewasrelated tomodafinil. Of thefourserious adverse events thatoccurred duringthestudy taking behaviours. No differences betweengroups forASI,CGI,craving, orHIVrisk- participants andshowed betterstudyretention. longer duration ofconsecutive non-using days thanlesscompliant Participants whowere compliantwithmodafinildosinghada at the completion of the study as assessed by urine screens. number of methamphetamine non-use days or on ‘terminal abstinence’ groups on methamphetamine non-use weeks overall or on maximum free weeks over the duration of the study, with no differences between Participants in all three groups had an increase in methamphetamine- Summary Measures Primary outcomesincludingmeasures used trial randomised controlled placebo- double-blind multi-site Level II— evidence Level of reported. sites andwell across eight well conducted study thatwas High-quality assessment Quality

69 Appendix: Summary tables Summary Appendix: 70 Medication treatment options for amphetamine-type stimulant users America United Statesof 35(1): 34–37. Alcohol Abuse of Drug and American Journal men: a pilot study. use in HIV+ gay methamphetamine therapy for behavioral plus cognitive (modafinil) al. (2009). Provigil McElhiney, M.C. et America United Statesof 109(1–3): 20–29. Dependence, Drug andAlcohol dependence. methamphetamine the treatment of of modafinilfor controlled trial placebo- double-blind, Randomized, Medicine et al.(2010). Heinzerling, K.G. Reference , oaii 13 gay men n=11 (85%) HIV+ Modafinil oaii 71dependent Modafinil 12 Mean use inlast30 days: 43 of abuse ordependence: Mean estimatedduration mine use: notreported Mean years ofmethampheta- Mean age:38(SD6)years Males n=13(100%) stimulant dependence (46%) abuse (54%) and n=6 DSM–IV n=7 with DSM–IV stimulant n=34 orplacebon=37 Randomised tomodafinil 9.4 Mean use inlastmonth: 15.6 methamphetamine use: Mean years of Mean age:39.1years Males n=50(70%) methamphetamine users of Number anddescription

participants

days months days

years to 200 others. Thedosewasincreased modafinil dosewas50 by fourweeks ofplacebo.Starting Twelve weeks ofmodafinilfollowed remaining 14weeks. by weeklyCBT sessions forthe enhancement emphasis followed weekly sessions withamotivational started withtwoweeks oftwice- The 16-weektherapy component side effects. clinical response andsignificant medications and100 for thosetakingHIVantiretroviral day forthefinalthree days. was titrated downto200 days ofthetrial,whendose in themorning)untillastthree tablets perdaytakenatonetime to 400 the studyfollowedby anincrease morning) forthefirst three days of 100 modafinil 200 Twelve weeks ofmedication: if Intervention andcomparison was $537 in vouchers). visits throughout the entire study metabolite-free urine samples at all providing methamphetamine- and maximum that could be earned for methamphetamine-free urines … the (vouchers for goods and services for study plus contingency management during the medication phase of the Weekly individual CBT sessions

relevant

mg/day intheabsenceof mg perday(four100 tablets per day taken in the

mg perday(two

mg/day for

mg/day

mg per

mg Summary medication adherence. craving measured weeklyusing avisual analoguescale;pillcountfor and psychiatric; BeckDepression Inventory (BDI);methamphetamine medical; employment; druguse; alcoholuse; legal;family/social; severity ofaddiction-related problems inseven areas offunctioning: Urine samples collectedthree timesaweek;ASI–Litetomeasure the Measures low-baseline methamphetamine use (x2=3.8, d.f.=69, p=0.05). more likely to have low CBT attendance in comparison with those with Participants with baseline high-frequency of methamphetamine use were ticipants in the placebo group received $139 (t=–0.70, d.f.=69, p=0.49). tion reinforcing methamphetamine-free urine drug screens, while par- $113 of the $537 possible from the contingency management interven- between groups. Participants in the modafinil group received on average phetamine cravings decreased but there were no significant differences but there were no significant differences between groups. Metham- Depressive symptoms decreased during the medication treatment period, depression or craving. There were no medication-related adverse events. There were no differences between the groups on drug use, retention, participants (77%)completed the16-weektrial. address sexualissues appears topromote treatment retention. Ten agent, whichcanthenbediscontinued. Theaddition ofCBT to and maybemosteffective asashort-term abstinence-induction useful topatientswithadiagnosis ofabuse rather thandependence week. Theauthors concludedthatmodafinilappeared tobemore showed agreater than50%reduction inmethamphetaminedays per Results are provided forcompleters only. Sixofthe10 completers Summary for methamphetamine. Cocaine Craving Scale;Obsessive Compulsive DrinkingScaleadapted Rating ScaleforDepression (HAM–D);University ofMinnesota Urine drugscreen; methamphetamineuse self-report; Hamilton Measures Primary outcomesincludingmeasures used RCT controlled placebo- blind, — double- Level II pilot subjects blind within — single Level III–3 evidence Level of interventions. behavioural in intensive participated All groups 35% placebo). modafinil and completion (41% low treatment sample size,but reasonable RCT with A well-conducted other studies. compared to dose ofmodafinil participants. Low ATS-dependent number of only. Small of completers sample. Analysis with small a Level IIIpilot Well conducted, assessment Quality

71 Appendix: Summary tables Summary Appendix: 72 Medication treatment options for amphetamine-type stimulant users (200 mg/day)for of modafinil controlled trial blind, placebo- (2009). Adouble- Shearer, J.etal. Australia 224–233. Addiction, 104(2): dependence. methamphetamine America United Statesof 488–491. cology, 29(5): Psychopharma- Journal ofClinical mine dependence. methampheta- of modafinilfor label pilotstudy Medicine (2009). Open- McGaugh, J.etal. Reference oaii 80dependent Modafinil Seven dependent Modafinil 7 methamphetamine use: Mean years of Mean age:35.9years Males n=50(62.5%) methamphetamine users 20.1 (8.25)days Mean use inlast30days: reported methamphetamine use: not Mean years of Mean age:45.3years Males n=3(43%) methamphetamine users of Number anddescription n=38 orplacebon=42 Randomised tomodafinil 19.4 days Mean use inlast28days:

years

participants if Intervention andcomparison for methamphetamineusers. intervention developed specifically four-session cognitive behavioural All participantswere offered abrief adherence. record unsupervised regimen system (MEMS)capbottlesto medication event monitoring weekly for10 weeks using Modafinil 200 cognitive behaviour therapy sessions. weekly for analysis, and attending submitting urine samples thrice returning medication blister packs, monetary rewards in exchange for plus contingency management with alised CBT for relapse prevention Weekly manual-driven, individu- after modafinil was discontinued. observed for five days during week 6 on modafinil for five weeks and then 400 first three days, then increased to modafinil 200 Participants were started on

relevant

m g daily. They were maintained

m mg/day dispensed g daily for the and HAM–Adecreased significantly. positive urinescreens didnotchange.Scores onboththeHAM–D self-reported methamphetamineuse decreased butamphetamine- efficacy ofmodafinilformethamphetaminedependence,however the course ofthestudy. Thestudywasnotdesignedtotestthe both theHamiltonanxietyanddepression scalesdecreased over Although anxietyis apotentialsideeffectofmodafinil, ratings on among asample ofeightmethamphetamine-dependentoutpatients. Study showed thetolerability andsafety ofmodafinil400mg/day Summary effects checklist. depression andanxietyscales(HAM–D/HAM–A),modafinilside amphetamine use weeklyusing analoguescales;weeklyHamilton Urine screen andvitalsignmeasure three timesaweek;self-reported Measures group hadpoorer methamphetamineuse outcomes. HIV-positive participants whowere over-represented inthemodafinil by sixdays (95%CI:–10.8, –1.8). Simply attendinganyformof counselling reduced 28-dayself-report report by one day(95%CI:–1.7,–0.3)atpost-treatment follow-up. during the10-week treatment periodreduced 28-daystimulant self- Regardless ofgroup allocation,eachsession ofcounselling attended Drop-out rate wasvery high(more than60%). those whoaccessedcounselling. Themedication waswelltolerated. dependent participantswithnoothersubstancedependence and urine samples. Outcomeswere betterformethamphetamine- compliant participantstoprovide more methamphetamine-negative adherence. There wasanon-significant trend formedication- craving, severity ofdependence,treatment retention ormedication There were nodifferences inmethamphetamine abstinence, Summary during treatment; adverse events. on a100-mm visual analoguescale(VAS);weeklyurinespecimens Dependence Scale(SDS);methamphetaminecraving inthepastweek 28-day druguse diaries;BriefSymptomInventory (BSI);Severity of Self-reported ATS use: TheOpiateTreatment Index(OTI) and Measures Primary outcomesincludingmeasures used RCT (pilot) controlled placebo- double-blind group a control without clinical trial open-label Level IV— Level II— evidence Level of used. ITT analysis was adherence. low medication out rate and very highdrop- study witha Well-conducted label study. but small open- Well-conducted assessment Quality

73 Appendix: Summary tables Summary Appendix: 74 Medication treatment options for amphetamine-type stimulant users Bupropion America United Statesof 991–1000. men. AIDS,24(7): who have sex with high-risk men dependence in methamphetamine Medicine Reference intervention for pharmacologic randomized of aphaseII and acceptability (2010). Feasibility Das, M.etal. urpo 30mendependent Bupropion (43% methamphetamine months whileusing men inthepastthree who hadanalsexwith methamphetamine users placebo (n=10) bupropion (n=20)or Randomised to a weekn=16(57.5%) n=14 (42.5%);3–7days less than3days aweek Mean use inlastmonth: reported Mean years ofuse: not Mean age:35.7years Males n=30(100%) of participants Number anddescription

HIV+) one-off) reported, butpossibly clinician (frequency not counselling by thestudy plus medicationadherence methamphetamine use, counselling sessions for weekly 30-min.CBT/MI week 2to12,plus increased to300 daily foroneweek, matching placebotaken Primaryoutcomesincludingmeasures used Bupropion 150 comparison ifrelevant Intervention and

mg and

mg from adverse events by treatment assignment. No serious adverse events occurred andthere were nosignificantdifferences in median numberofsexpartners. (50%). Participants inbotharms reported similarnon-significant declineinthe The mediannumberofpositive urinesamples was5.5outofapossible11 differ significantly by treatment assignment. Adherence by MEMScapwas 60% andby self-report was81% anddidnot 81% ofstudyvisits were attended;and81% ofurinesamples were collected. Ninety percentcompletedthetrial:89%ofmonthlyACASIs were completed; engage group ofmethamphetamineusers intotreatment. study demonstrates thefeasibilityofenrolling andretaining atypicallyhard-to- highly satisfied or satisfied withstudyparticipation.Authors conclude thatthe adverse events from themedications. Ninety-sixpercentof participants were screens, sexualrisk-taking behaviours, ordepression. There were noserious on self-report), reduction inmethamphetamine-metabolitepositive urinedrug medication adherence (bothgroups over-estimated theirmedicationadherence difference betweenthetwogroups intreatment completion,self-reported Both groups showed improvements onallmeasures. There wasnosignificant Summary reasons fornon-adherence; attitudesabouttrialparticipation. Epidemiologic StudiesDepression RatingScale(CES–D);sexualrisk behaviour; drug use; AODtreatment; Severity ofDependenceScale(SDS);Centerfor — frequency androute ofadministration ofmethamphetamineandother use, risks, depression using audiocomputer-assisted self-interview(ACASI) Severity ofAdult Adverse ExperiencesforHIVPrevention Trials Network.Drug and 12classifiedaccording toDivision ofAIDS(DAIDS) Table forGrading physical exams andsafety laboratory monitoringwere done at weeks 4,8, Structured Self-Report;medicationsafety –weeklyself-report, symptom-driven Medication adherence –MEMScaps, self-reported adherence using the 4-day Measures pilot) (feasibility RCT controlled placebo- double-blind Level II– evidence Level of + person. assessed in 56% forthose rate (9%),but randomisation pre-screen to Low phone adherence. medication to moderate rates, butlow study completion sample size.Good pilot study. Small A well-conducted assessment Quality

75 Appendix: Summary tables Summary Appendix: 76 Medication treatment options for amphetamine-type stimulant users America United Statesof data analysis.) above fororiginal et al.(2008) (Also seeElkashef 18(5): 414–418. and Therapeutics, CNS Neuroscience multisite trial. reanalysis ofa dependence: methamphetamine Medicine Reference efficacy versus bupropion failure reveals success and evaluation of novel, nonbinary Li, S-H.(2012). A McCann, D.J.& America United Statesof 1162–1170. macology, 33(5): Neuropsychophar- mine dependence. methampheta- the treatment of Bupropion for et al.(2008) Elkashef, A.M. urpo 151 dependent Bupropion urpo 151 dependent Bupropion placebo (n=72) bupropion (n=79)or Randomised to days: 17days Mean use inlast30 10.42 years methamphetamine use: Mean years of Mean age:36years Males n=101 (67%) methamphetamine users of participants Number anddescription placebo n=72 buproprion n=79or Randomised to (53%) and >18days n=80 ≤18 days n=71 (47%); Mean use inlastmonth: 10.19 Mean years ofuse: Mean age:36years Males n=101 (67%) methamphetamine users

years increased to300 daily forthree days, then SR orplacebo,once of bupropion 150 Participants received doses and matchedplacebo. bupropion 150 Sustained-release Model) for12weeks. times aweek(Matrix group-based CBT three 90 mins ofmanualised, All participantsreceived count. assessed by weeklytablet period. Adherence was the 12-weektreatment on thelastthree days of reduced to150 dose taper. Thedosewas treatment, untilthefinal for about11 weeks of (one tablettwiceaday) Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and Model) for12weeks. times aweek(Matrix group-based CBT three 90 mins ofmanualised, All participantsreceived treatment period three days ofthe12-week 150 then dosewasreduced to twice aday)for11 weeks, 300 daily forthree days, then or matchedplaceboonce release bupropion 150 Film-coated sustained-

mg dailyonthelast mg daily(onetablet

mg mg daily

mg daily

mg treatment failures reporting this level of baselineuse (40%;P=0.04). methamphetamine use (69%)wassignificantlygreater thantheproportion of the proportion of‘treatment successes’reporting 18days orlessofbaseline of methamphetamineuse duringthe30days immediatelybefore screening; ‘successful outcome’withbupropion treatment wastheself-reported level during thetrial),onlyfactorthatwassignificantlyassociated witha of methamphetamineabstinenceduringthetrial(range 2–12weeks Of the16treatment participantswhodidattain two ormore weeks group, only7%(5/72)were abletoachieve twoormore weeks ofEOSA. study weeks 4–6,whichthenincreased steadilyto20%(16/79).Intheplacebo seemed toincrease inabiphasicfashion, withaplateauat11% (9/79) from Throughout thecourse ofthestudy, thesuccess rate inthebupropion group medicine totreat alcoholandtobaccodependence. demonstrate apositive effect of bupropion basedonFDAevaluations of from bupropion. Thecurrent paper used adifferent methodofanalysis to to demonstrate aneffectforbupropion, butfoundsomesubgroups benefited This studyre-analysed datafrom Elkashef etal.2008.Theoriginalstudy failed Summary report ofmethamphetamineuse (TLFB);Addiction Severity Index(ASI–Lite). Substance Craving Scale(BSCS);HamiltonDepression Scale(HAM–D);self- Primary outcomeassessment wasurinedrugscreens three timesperweek;Brief Measures methamphetamine dependenceinmalepatients. the numberofweeks ofabstinenceinparticipantswithlow-to-moderate in combinationwithbehavioural group therapy, waseffective forincreasing methamphetamine use atbaseline.Theauthors concludedthatbupropion, effect, compared toplacebo,amongmalepatientswhohadalowerlevel of use week,butsubgroup analysis showed thatbupropion had asignificant There wasnosignificantdifference betweengroups onprobability ofanon- Summary (ASI–Lite); adherence wasassessedby weeklytabletcount. Depression Scale(HAM–D);Timelinefollow-back;Addiction Severity Index week formethamphetamine;BriefSubstanceCraving Scale(BSCS);Hamilton Percentage ofabstinencewasmeasured by urinedrugscreens three timesa Measures RCT controlled placebo- double-blind, RCT controlled placebo- double-blind Level evidence Level of Level II–

— application. limited clinical for successhave 2008). Criteria (Elkashef etal. double-blind RCT well-conducted, reanalysis ofa Complex ++ double-blind RCT. A well-conducted, assessment Quality

77 Appendix: Summary tables Summary Appendix: 78 Medication treatment options for amphetamine-type stimulant users America United Statesof 96(3): 222–232. Dependence, Drug andAlcohol dependence. methamphetamine Medicine Reference the treatment of of bupropion for controlled trial placebo- Randomized, et al.(2008). Shoptaw, S. urpo 73dependent Bupropion placebo (n=37) bupropion (n=36)or Randomised to days: 15.6days Mean use inlast30 9.6 years methamphetamine use: Mean years of Mean age:34.6years Males n=22(61%) (64%) of methamphetamine predominantly smokers recruited from three sites, methamphetamine users of participants Number anddescription 150 Slow-release bupropion $537) urine screens (max.value methamphetamine-free Non-cash vouchers for sessions for12weeks Weekly individualCBT last three days of bupropion SRforthe was decreased to150 week 12whenthedose taken twicedaily)until day (one150 increase to300 first weekfollowed by an day fordays 1–3ofthe Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and

mg (orplacebo)per

mg capsule

mg per

mg treatment-related serious adverse effects. of counselling sessions attended(5/12forbupropion, 4/12forplacebo).No craving, whichdecreased amongbothgroups. Nodifferences inthe number decreased amongbothgroups. Nosignificantdifferences inmethamphetamine five cigarettes perday. Nosignificantdifferences indepression scores, which was also associatedwithsignificantly reduced cigarette smoking, by almost methamphetamine-positive urines)use atbaseline.Bupropion treatment with lighter(0–2methamphetamine-positive urines),butnotheavier(3–6 treatment onmethamphetamineuse andcompletionrates amongparticipants In aposthocanalysis, there wasastatistically significanteffectof bupropion of depressive symptoms ormethamphetaminecravings, oron studyretention. methamphetamine use verified by urinedrugscreens, for reducing theseverity There were nosignificanteffectsforbupropion relative toplacebo on Summary cravings (visual analoguescale);andadverse events. depressive symptoms (BeckDepression Inventory —BDI);methamphetamine Methamphetamine use asassessedviaurinedrugscreens; treatment retention; Measures RCT controlled placebo- double-blind Level II— evidence Level of (around 35%). completion rates trial, butlow well-conducted High-quality assessment Quality

79 Appendix: Summary tables Summary Appendix: 80 Medication treatment options for amphetamine-type stimulant users Naltrexone Sweden 59(3): 167–171. Journal ofPsychiatry, tolerability. Nordic compliance and dependence: for amphetamine trial ofnaltrexone An openclinical Franck, J.(2005). P., Beck,O. & N., Wennberg, Jayaram-Lindström, placebo- ence: a randomized, amphetamine depend- for the treatment of et al. (2008) Naltrexone Jayaram-Lindström, N. America United Statesof 20(11): 823–828. chopharmacology European Neuropsy- mine dependence. one for methampheta- cysteine plus naltrex- led study of N-acetyl blind, placebo-control- (2010). A double- Grant, J.E. et al. Reference Sweden 442–448. of Psychiatry trial. American Journal c ontrolled , 165(11): , ateoe20dependentmethamphetamineusers who Naltrexone naltrexone (NAC) plus cysteine N-acetyl Numberanddescriptionof Medicine ateoe80dependentamphetamineusers Naltrexone Mean use inlastmonth:notreported reported Mean years ofmethamphetamineuse: not Mean age:notreported Males n=13(65%) the last12weeks had used amphetamineatleast12days in Randomised to naltrexone n=40, placebo n=40 NAC +placebo(n=17) Randomised toNAC+naltrexone (n=14)or two weeks: 7.18days Mean days used methamphetamineinpast reported Mean years ofmethamphetamineuse: not 24.2 years Mean agefirst used methamphetamine: Mean age:36.6years Males n=22(71%) 31 dependent methamphetamineusers weeks: 45.4days Mean days ofamphetamine use inlast12 Mean use inlastmonth: notreported 10.19 years Mean years ofmethamphetamineuse: Mean age:39.4years Males n=63(79%)

participants relapse prevention individualised CBT for weekly ofmanual-driven 12 weeks, plus 30mins dispensed weeklyfor 50 relapse prevention weekly manualised CBT-based 60 mins ofindividual matching placebo,plus daily for12week 50 1200 for twoweeks, then Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and for thefinaltwoweeks 200 2400 for twoweeks, andto 150 1800 for twoweeks, and 100 50 600

mg naltrexone daily, mg naltrexone mg/day naltrexone

mg/day naltrexone mg/day naltrexone mg/day naltrexone mg/day NACplus

mg/day NACplus mg/day NACplus mg/day NACplus s and Measures Summary and medicationadverse events. amphetamine use (TLFB);Craving Visual AnalogScale(VAS); Urine drugscreens; Addiction Severity Index(ASI);self-reported Measures groups over 12 weeks. Treatment was well tolerated. increase in mean amphetamine-negative urine screens among both reduced craving. There was an effect for time in treatment with an reported amphetamine use, better retention in treatment and Naltrexone resulted in higher negative urine screens and self- naltrexone, even when all but two continued to use amphetamines. to those who did not (77% vs 22%); 90% of participants tolerated urine among patients completing 12 weeks of treatment compared nificantly higher proportion of positive tests of 6-beta-naltrexol in craving scores also decreased among completers. There was a sig- during treatment compared with pre-treatment consumption, and quency and amount of amphetamine used were significantly lower Eleven participants (55%) completed the 12-week study. The fre- Summary for naltrexone metabolites; number of treatment days attended. weeks 4, 8 & 12; adherence — self-report; pill counts; urine screen tolerability of naltrexone — adverse events (AE) blood samples Scale (VAS); weekly urine screen for illicit drugs and naltrexone; Self-reported amphetamine use (TLFB); Craving Visual Analog methamphetamine-dependent individuals. significantly reduce craving amongnon-treatment-seeking The authors concludedthataddingnaltrexone toNACdidnot There were nodifferences betweengroups onanymeasures. Summary (SDS); theQualityofLifeInventory (QoLI). Rating ScaleforAnxiety(HAM–A);SheehanDisability Scale Hamilton RatingScaleforDepression (HAM–D);Hamilton drug screen; ClinicalGlobalImpression (Severity) scale(CGI); Penn Craving Scale;frequency ofmethamphetamineuse; urine Measures RCT controlled placebo- double-blind, Level (feasibility) group control without clinical trial open-label Level IV– RCT (pilot) controlled placebo- double-blind, evidence Level of Level

II II

— — drop-out. size andhigh small sample trial, but feasibility conducted Well- drop-out. high moderately size but good sample study with conducted Well- drop-out. size andhigh Small sample pilot study. conducted A well- assessment Quality

81 Appendix: Summary tables Summary Appendix: 82 Medication treatment options for amphetamine-type stimulant users Antipsychotics Reference America United Statesof 167–172. Drugs, 39(2): of Psychoactive dependence. Journal methamphetamine the treatment of of risperidone in label pilotstudy (2007). Anopen- Meredith, C.etal. America United Statesof 751–761. Addiction, 108(4): controlled trial. blind, placebo- randomized, double- dependence: a methamphetamine for thetreatment of (2013). Aripiprazole Coffin, P.O. etal. Medicine iprdn 11 dependentmethamphetamine Risperidone rppaoe90dependentmethamphetamine Aripiprazole of Number anddescription days Mean use inlast30days: 9.9(7.6) use: 8.5(6.3)years Mean years ofmethamphetamine Mean age:42years Males n=10 (90.9%) users or placebo(n=45) Randomised toaripiprazole (n=45) exclusion criteria. count below200cells/μl were past fourweeks andaCD4cell psychiatric medicationwithinthe Major depression, history of use: notreported Mean years ofmethamphetamine days orlessn=28(31.1%) 3–6 days weekn=43(47.8%);2 in past4weeks: dailyn=19(21%); Frequency ofmethamphetamine Mean age:38.7years Males n=79(87.8%) users

participants oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and occurred. intolerable sideeffects was decreased if The doseofrisperidone weeks. on risperidone forfour psychiatrist andremained weekly visits withastudy Participants attended highest tolerated dose). days to4 dose escalationover four before sleeping) with 1 Participants startedon 5 counselling and MIsubstanceabuse Weekly 30-minuteCBT 12-week study for theremainder ofthe week, then20 10 mgdailyforthenext (or placebo)foroneweek,

mg nightly(onedose mg dailyofAripiprazole

mg nightly(or

mg daily mean dailyrisperidone dose of3.6mg(SD=0.52). during thestudy. Participants completingthestudyhad afinal population. Participants continuedwithpsychological therapy draw clearconclusions abouttheefficacyofrisperidone inthis study itselfrather than therisperidone. This makes itdifficultto increased accessand supportasaresult ofparticipationinthe possible thattreatment effectsmayhave occurred duetothe significant reduction indays ofmethamphetamine use. It is Risperidone waswelltolerated andtreatment completers showed Summary language and verbal fluency, and psychomotor function. learning and memory, executive functioning and abstraction, a range of functions including speed of information processing Inventory (BSI), a neuropsychological testing battery that assessed of adverse events and concomitant medication use; Brief Symptom monitored urine drug screen, self-reports of substance use, reports abuse history, and medications; weekly measures of vital signs Clinical charts, which included demographics, medical and substance Measures (408 sessions), placebo80%(431 sessions); p=0.11). sessions (839outof1080) were completed(aripiprazole 76% significantly different; 78%ofweeklysubstance use counselling and self-report waslowat42%and74%respectively, butnot fatigue anddrowsiness thanplacebo.Adherence by MEMS measures. Aripiprazole participantsreported more akathesia, to placeboinreducing methamphetamineuse oranyoftheother craving andseverity ofdependence.Aripiprazole wasnotsuperior Both groups reduced methamphetamineuse, sexualrisk taking, Summary Dependence Scale(SDS). risk-taking behaviour;methamphetaminecraving; Severity of (self-report andmedicationevent monitoringsystem); sexual Urine drugscreens formethamphetamine;medicationadherence Measures trial randomised controlled placebo- double-blind group a control without clinical trial open-label Level IV— vdneQualityassessment evidence Level of Level II— adherence. low medication retention butfairly RCT withgood double-blind and -reported Well-conducted timeframe. term follow-up group andshort- lack ofcontrol small sample size, study includea Limitations ofthis low-level study. A well-conducted

83 Appendix: Summary tables Summary Appendix: 84 Medication treatment options for amphetamine-type stimulant users Reference America United Statesof 55–65. Medicine, 3(2): Journal ofAddiction dependence. methamphetamine risperidone for trial ofinjectable al. (2009).Open Meredith, C.W. et Finland 160–162. Psychiatry, 164(1): American Journalof dependence. amphetamine and placebofor methylphenidate, aripiprazole, comparison of al. (2007).A Tiihonen, J.et phenidate methyl Aripiprazole, Medicine iprdn 34dependentmethamphetamine Risperidone 53 dependentamphetamineu (n=17) methylphenidate (n=17)orplacebo Randomised toaripiprazole (n=19), use: approx. 14years Mean years ofmethamphetamine Mean age:32.2years Males n=36(68%) of Number anddescription Mean use inlast30days: 17.1days use: 12.2years Mean years ofmethamphetamine Mean age:38years Males n=19(86.4%) injectable risperidone users entered thestudy, 22received

participants sers week, and54 placebo Equivalent gelcapsule thereafter 36 day forthefirst week, Methylphenidate 18 Aripiprazole 15 oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and prevention counselling. sessions ofrelapse eight weeklyindividual Participants were offered initial injection. the first three weeks after oral risperidone during Participants remained on of fourinjections. every twoweeks toatotal with subsequentinjections intramuscular medication risperidone 25 long-acting injectable (n=22) were startedon tolerated oral risperidone risperidone. Thosewho label run-inwithoral a seven-day open- Participants entered

mg/day forthesecond

mg/day

mg/ analysis reported aripiprazole significantlyworsened symptoms. urine samples thanplacebo.Thetrialwasceased afterinitial methylphenidate hadsignificantlyfeweramphetamine-positive amphetamine-positive urinesamples and thosewhoreceived Patients allocatedtoaripiprazole hadsignificantlymore Summary treatment. amphetamine-positive urinesamples duringpharmacological The primaryoutcomemeasure wastheproportion of Measures symptoms. Improvements were seeninverbal memoryandpsychiatric was significantly reduced amongthosewho received injections. No serious adverse events occurred. Methamphetamineused Summary Scale were administered toassessmovement disorders. Simpson–Angus Scale;andtheAbnormalInvoluntary Movement (ASI); BriefSymptomInventory (BSI);BarnesAkathisia Scale; days; aneurocognitive testbattery;Addiction Severity Index methamphetamine andothersubstanceuse over theprior60 60-day timelinefollow-backinterviewtoquantifyself-reported serum prolactin levels. Inaddition:Structured ClinicalInterview; history, physical examination androutine laboratory tests, and At screening, allparticipantsreceived acompletemedical Measures trial randomised controlled placebo- double-blind Level II— vdneQualityassessment evidence Level of group a control without clinical trial open-label Level IV— analysis. missing datafor high proportion of sample sizeand analysis butsmall study withITT A well-conducted the finalN is small. commencement, were higheratthe though numbers retention and difficulties with study. There were but low-level A well-conducted

85 Appendix: Summary tables Summary Appendix: 86 Medication treatment options for amphetamine-type stimulant users Anticonvulsants America United Statesof 1297–1306. Addiction, 107(7): controlled trial. placebo- multi-center addiction: a methamphetamine Medicine Reference the treatment of Topiramate for et al.(2012). Elkashef, A. oiaae140dependent Topiramate 21.3 Mean use inlastmonth: Mean years ofuse: notreported Mean age:38years Males n=89(64%). methamphetamine users (n=69) orplacebo(n=71) Randomised totopiramate of Number anddescription

participants

days was tapered to100 treatment (week13),thedose included. Over thelastweekof those tolerating >50 previously tolerated dose.Only maintenance, tothehighest could bereduced onceduring dose wasmaintained.Daily achieved. Over weeks 6–12,this the maximumtolerable dosewas retention. medication adherence and supportive program topromote a manualised, low-intensity enhancement treatment (BBCET), brief behavioural compliance All participantsreceived weekly measured by pillcount. days. Medicationadherence was days andthen25 three days, 50 the studyupto200 escalated over thefirst 35days of initiated at25 Oral topiramate orplacebowas if Intervention andcomparison

relevant

mg/day fortwo mg/day and

mg/day fortwo

mg/day for

mg/day or mg/day were drop-out rate. 67.4% forplacebo.Nosignificantdifference between groups in tolerated. Meanadherence rate was69.8%fortopiramate and decreasing craving over time.Topiramate wassafe andwell dependence, measured by CGI–O, anon-significanttrend toward significant improvement inobserver-rated globalseverity of to abstinenceinweeks 6–12.Topiramate recipients experienced functioning compared toplacebo.Abstinenceatentrywasrelated in reducing use, severity ofdependenceandimproving general in increasing abstinence,butthere were significant reductions completer-only analysis. Studyshowed noeffectfortopiramate topiramate; 53placebo).ITTanalysis showed similarresults to included intheanalysis (n=111 (79.3%)were evaluated: 58 took >50mg/dayoftopiramate (orplacebo)for21 days were Participants whocontributed>6usable urinesamples and Summary adherence by pillcount. Asberg Depression RatingScale;druguse self-report; medication Scale (BSCS);Addiction Severity Index(ASI–Lite);Montgomery– Observer (CGI–O)andSelf(CGI–S);BriefSubstanceCraving Secondary assessments: ClinicalGlobalImpression Scale— week for%ofabstinence. Primary outcomeassessment: urinedrugscreens three timesa Measures Primary outcomesincludingmeasures used Level II– evidence Level of RCT controlled placebo- multi-site double-blind assessment Quality on completers. conclusions based conducted but ITT analysis rate (55%),and Low completion multi-site RCT. A well-conducted

87 Appendix: Summary tables Summary Appendix: 88 Medication treatment options for amphetamine-type stimulant users America United Statesof 122–125. Synapse, 55(2): addiction. and/or cocaine methamphetamine the treatment of GABA (GVG)for gamma vinyl and efficacyof al. (2005).Safety Brodie, J.D.et America United Statesof 85(3): 177–184. Dependence, Drug andAlcohol dependence. methamphetamine Medicine Reference the treatment of gabapentin for of baclofenand controlled trial placebo- Randomized, et al.(2006). Heinzerling, K.G. (GVG)) Vinyl GABA (Gamma Vigabatrin gabapentin and Baclofen nearly 1 Mean dailyreported use of 12.8 methamphetamine use: Mean years of Mean age:notreported Males n=29(96%) cocaine-dependent study; 17participantswere also entered and18completedthe methamphetamine-dependent 30 participants:n=27 9.5 methamphetamine use: Mean years of Mean age:32years Males n=61 (69%) methamphetamine users 88 dependent for 12years (n=37) gabapentin (n=26)andplacebo Randomised tobaclofen(n=25), approx. 15days Mean use inlastmonth: of Number anddescription

participants

years

g ofmethamphetamine were placedon3 week. Onday15,participants days and2 the dose was decreased to 400 800 1–3 of the first week followed by Or gabapentin 400 last three days first weekfollowed by 20 day (tid)fordays 1–3ofthe many didparticipate). therapy (no indicationofhow to participateinweeklygroup All participantswere encouraged dose of137 Completers received acumulative to zero over thenextthree weeks. next 28days, andthentapered maintained atthatdoseforthe then 1.5 mg twicedailyforthree days, Vigabatrin wasinitiatedat500 prevention group sessions. of thrice-weekly, 90-min. relapse counselling program, consisting manual-driven psychosocial All participants received a standard medication inblister packages. dispensed aone-weeksupplyof study physician andthenwere taken undersupervision ofthe blister packages. First dosewas Medication wasdispensed in tid for the last three days decreased to10 until week16whenthedosewas Baclofen 10 if Intervention andcomparison

relevant

m g tid until week 16 when

g/day forthenextfour

g/day forthenext

mg three timesper g.

mg tidforthe

g/day,

m g tid for days

mg tid

m g craving agentformethamphetamine-dependentindividuals. but theshort half-lifeofbaclofenmaylimititsuse asananti- baclofen mayhave asmall treatment effectrelative toplacebo, groups. Theauthors concludedthat sample duringthetreatment period,butnodifference between a higherprobability ofproviding amethamphetamine-free urine baseline methamphetamineuse were significantlyassociatedwith at counselling sessions, lower depression symptoms and less severe medication takenorpsychosocial sessions attended.Attendance reductions inuse compared toplacebo.Nodifferences in a higher baclofen, butnotgabapentin,participantswhoreported taking in reducing methamphetamineuse, craving orretention. For There were nosignificantmaineffectsforbaclofenorgabapentin Summary analogue scale;pillcountformedicationadherence. methamphetamine craving measured weeklyusing avisual family/social, andpsychiatric; BeckDepression Inventory (BDI); functioning: medical,employment, druguse, alcoholuse, legal, the severity ofaddiction-related problems inseven areas of Urine samples collectedthree timesaweek;ASI–Litetomeasure Measures Primary outcomesincludingmeasures used Summary Urine samples twiceaweek;dailyvitalsigns. Measures to beeffectiv The median onset time to the first day drug-free was 10 days. use of 0.03 +/– 0.02 g/day over the last three weeks of the study. drug-free interval was 40.1 +/– 2.4 consecutive days with an average free although use was markedly reduced by self-report. The mean free for four consecutive weeks (no slips) while two were never drug- under supervision, completers were methamphetamine- and cocaine- weight gain over non-completers. Based on urine samples taken Completers reported increased appetite and showed a significant vigabatrin is safe to use with methamphetamine and cocaine users. use of methamphetamine and cocaine. The authors concluded that tions in visual acuity or changes in vital signs even with continued At this dose GVG did not produce any visual field defects or altera- per centage ofstudymedicationshowed significant e intreating methamphetaminedependencebut gabapentin doesnotappear RCT controlled placebo- blind, — double- Level II evidence Level of safety trial open-label Level IV— completion). placebo 40% completion, and gabapentin 35% 60% completion, variable (Baclofen out highand study, but drop- A well-conducted assessment Quality + users. amphetamine separately for were notreported Outcome data control group. drop-out andno but withhigh open-label study, briefly reported Well-conducted,

89 Appendix: Summary tables Summary Appendix: 90 Medication treatment options for amphetamine-type stimulant users Antidepressants to reduce Mirtazapine et al.(2011). Colfax, G.N. America United Statesof 1168–1175. Psychiatry, 68(11): of General trial. Archives controlled use: arandomized methamphetamine America United Statesof Acapulco, Mexico. Drug Dependence, on Problems of of theCollege Annual Meeting presented atthe analysis. Paper a preliminary controlled trial: dependence —a methamphetamine Fluoxetine in Medicine al. (1999). Batki, S.L.et Reference Mirtazapine Fluoxetine of Number anddescription (n=30) orplacebo Randomised tomirtazapine n=10 used (17%daily) used more than3timesaweek, Mean use inlastmonth:60% Mean years ofuse: notreported Mean age:40.5years Males n=60(100%) 200/μL, were excluded. with aCD4cellcountbelow weeks, andHIV-positive men antidepressant use inlastfour Those withmajordepression or MSM users whowere sexuallyactive 60 dependent methamphetamine daily orplacebo(n=30) used per week: 2.4 Mean amount methamphetamine methamphetamine use: 2.6days Mean days perweek methamphetamine use: 7.4years Mean years of Mean age:35years Males n=42(70%) n=9 (15%) Gay bisexual n=21 (50%),HIV+ users 60 dependent methamphetamine Randomi

participants sed tofluoxetine (n=30)

g if Intervention andcomparison 11 administered: 1capsule(15 mirtazapine orplacebowere Gel capsulescontainingeither double-blind fluoxetine 40 lead-in followedby seven weeks of One weeksingle-blindplacebo MI-based counselling. 30-minute substanceuse CBT and All participantswere offered weekly 2 nightly foroneweek,andthen or placebo

capsules (30 relevant

weeks.

mg) nightlyfor

mg daily mg) Primary outcomesincludingmeasures used differences in adverse events by arm. were no serious adverse events related to study drug or significant episodes of insertive anal sex with serodiscordant partners). There episodes of unprotected anal sex with serodiscordant partners, male partners, episodes of anal sex with serodiscordant partners, partners with whom methamphetamine was used, number of significantly more among the mirtazapine group (number of male different between arms. Sexual risk behaviours decreased systems and 74.7% by self-report; adherence was not significantly was 3.1. Adherence was 48.5% by medication event monitoring number needed to achieve a negative weekly urine test result positive urine test results compared to the placebo group. The mirtazapine group had significantly fewer methamphetamine- and sexual risk-taking behaviours. Participants assigned to the Mirtazapine group significantly decreased methamphetamine use Summary study medicationadherence andsexualrisk behaviour. metabolite-positive urinetestresults. Secondaryoutcomeswere Primary outcomewasreduction inmethamphetamine Measures reporting. Noadverse events datareported. the 30participantsforwhomdatawere available atthetimeof methamphetamine use orinmethamphetamineurinescreens for significant differences betweenthegroups onself-reported was lowerinactive treatment group butnoother Methamphetamine use declinedinbothgroups. Craving Summary urine screens formethamphetamine. Methamphetamine craving; self-reported methamphetamineuse; Measures RCT controlled placebo- double-blind pilot RCT controlled placebo- double-blind evidence Level of Level II– Level II— ++ adherence. low medication but moderate to retention rates, study withgood and reported Well-conducted subsequently. was published of thedata detailed report proceedings. No the conference only reported in Preliminary data assessment Quality

91 Appendix: Summary tables Summary Appendix: 92 Medication treatment options for amphetamine-type stimulant users sertraline in response to (2011). Poor Zorick, T. etal. America United Statesof 500–503. 118(2–3): Dependence, Drug andAlcohol methamphetamine. craving for with sustained is associated dependence methamphetamine America United Statesof 85(1): 12–18. Dependence, Drug andAlcohol dependence. methamphetamine the treatment of management for contingency of sertraline and controlled trial placebo- Randomized, Medicine et al.(2006). Shoptaw, S. Reference etaie 229participants witha Sertraline 229participantswitha Sertraline or placebo-only(n=55) (n=59), placeboplus CM(n=54), CM (n=61), sertraline-only Randomised tosertraline plus approx. 13days Mean use inlast30days: methamphetamine use: 9.3years Mean years of Mean age:33years Males n=(60%) dependent) abuse ordependence(n=227 diagnosis ofmethamphetamine or placebo-only(n=55) (n=59), placeboplus CM(n=54), CM (n=61), sertraline-only Randomised tosertraline plus approx. 13days Mean use inlast30days: methamphetamine use: 9.3years Mean years of Mean age:33years Males n=(60%) dependent) abuse ordependence(n=227 diagnosis ofmethamphetamine of Number anddescription

participants groups three times a week. Matrix Model relapse prevention Plus all participants received 90-min. metabolite free urine sample. with US$10 bonus voucher each 3rd increasingly valuable (by US$1.25) (from US$2.50) which became qualified participants for a voucher metabolites of methamphetamine Fridays. Samples that did not contain on Mondays, Wednesdays and management observed urine samples Participants receiving contingency for the 12-week duration of the trial. increased to 50 following randomisation, dose was at randomisation. On the eighth day Sertraline or placebo at 50 was increased to50 day followingrandomisation, dose at randomisation. Ontheeighth Sertraline orplaceboat50 per prevention groups three times 90-min. MatrixModelrelapse Plus allparticipantsreceived third metabolite-free urinesample. with US$10 bonus voucher each increasingly valuable (by US$1.25) US$2.50), whichbecame qualified fora voucher (from methamphetamine metabolites and Fridays. Samplesfree of samples onMondays, Wednesdays participants observed urine Contingency management duration ofthetrial. daily maintainedforthe12-week if Intervention andcomparison

relevant

week.

m g bid maintained

mg twice

m mg/day g/day increased theirmethamphetamine use. specifically characterised participantsinthesertraline group who treatment. Elevated in-treatment craving formethamphetamine were associatedwithincreased methamphetamine use during factors from bothpre-treatment andin-treatment datathat placebo condition(n=5;p=0.03).Thestudylookedatmultiple methamphetamine use duringtreatment (n=13)thaninthe More participantsinthesertraline condition increased Summary this increase. of treatment inthetrial,participant-level factors associatedwith Increase inmethamphetamineuse >15% duringthelastmonth Measures participants in all other treatment conditions ( were retained in treatment for significantly less time than Drop-outs NS between groups, however sertraline-only participants (24/54), or placebo-only (22/55). sertraline plus CM (30/61), sertraline-only (35/59), placebo plus CM treatment (n=13) than in the placebo condition. Drop-outs: the sertraline condition increased methamphetamine use during abstinence than those in non-CM conditions. More participants in conditions achieved three consecutive weeks of methamphetamine conditions. A significantly higher proportion of participants in CM conditions produced significantly more adverse events than placebo retention than other conditions ( showed the sertraline-only condition had significantly poorer generalised estimating equation (GEE), although post hoc analyses or CM in reducing methamphetamine use were observed using a No statistically significant main or interaction effects for sertraline Summary and adherence to study medication (pill count, adverse events). for methamphetamine (visual analogue scale); depression (BDI); Methamphetamine use (urine screen); retention in treatment; craving Measures Primary outcomesincludingmeasures used χ 2(3) = 8.40, p <0.05). Sertraline χ 2(3) = 8.40, p <0.05). RCT controlled placebo- double-blind RCT controlled placebo- double-blind Level II— Level II— evidence Level of 50%). rates (around completion trial, butlow well-conducted High-quality Shoptaw (2006). Re-analysis of 50%). rates (around completion trial, butlow well-conducted High-quality assessment Quality

93 Appendix: Summary tables Summary Appendix: 94 Medication treatment options for amphetamine-type stimulant users Flumazenil andgabapentincombination America United Statesof 82(10): 1170–1178. Medicine Reference Clinic Proceedings dependence. methamphetamine dysregulation in acid receptor γ targeting type A treatment program a proprietary label study of al. (2007). Open- Urschel, H.C. et America United Statesof 361–369. Addiction, 107(2): dependence. methamphetamine protocol for the PROMETA™ evaluation of controlled blind placebo- (2012). Double- Ling, W. et al. -aminobutyric Mayo , gabapentin and Flumazenil gabapentin) and (flumazenil protocol Prometa™ 71.4 ±19.4days Mean use inpast90 days: not reported methamphetamine use: Mean years of years Mean age:35.2±7.3 Males n=26(52%) screening seven days priorto methamphetamine within users andhadused methamphetamine 50 dependent of participants Number anddescription hydroxyzine) (n=60) (n=60) orplacebo(with gabapentin/ hydroxyzine Randomised to flumazenil/ approx. 10 years methamphetamine use: Mean years of approx. 17.5days Mean use inpast30days: Mean age:38.5years Males n=89(80%) methamphetamine users 120 dependent to n=14). CBT-based relapse prevention sessions (up All participantsreceived weeklyindividual infusion on days 1, 2, 3, 22 and 23. home hydroxyzine to day 10 prior to each dose of oral hydroxyzine, with 50 placebo groups were administered a 50 Participants in both active treatment and medical procedures, and to assist with sleep. that might be experienced during the hydroxyzine in order to reduce the anxiety protocol, all participants received active considered the key element of the Prometa dose on day 40. As hydroxyzine is not day 38 with the final gabapentin or placebo study day 4. Down-titration began on study to reach the maximum dose of 1200 increasing by one capsule (300 1, participants began gabapentin or placebo, and 23 (or matched saline infusion). On day Flumazenil 2 11 weeklyindividualsupportsessions + Gabapentin upto1500 50 and 23 Flumazenil infusion ondays 1,2,3,22 Medication therapy forfourweeks: nevninadcmaio frlvn Primaryoutcomesincludingmeasures used Intervention andcomparison ifrelevant

mg oral hydroxyzine prior toinfusions

m g infusion on days 1, 2, 3, 22

mg daily

m g) per day

m g take-

g on m g publicity abouttheprotocol. influenced by astrong placeboeffectduetoconsiderable trial oftheprotocol, theirnullfindings mayhave been in comparison topositive outcomesfrom anotherrecent a meanof2.86sessions. Theinvestigators concludedthat, a meanof2.95sessions; andtheplacebogroup attended CBT sessionattendance:theexperimentalgroup attended baseline. Nosignificantdifference betweenthegroups in reported methamphetamineuse inthepast30days from to four-foldreduction inthenumberofdays ofself- All methamphetamine use, craving orretention intreatment. No effectoftheprotocol over placeboonmeasures of Summary the first infusion andthelastclinicvisit. (BSCS); retention measured by thenumberofdays between visit); self-reported druguse; BriefSymptomCraving Scale methamphetamine duringthetrial(collectedatevery clinic Percentage ofurinesamples testingnegative for Measures There were noserious adverse effects. results. 90%completedinfusions andoral medications. days andself-reported use was correlated withurinescreen methamphetamine use from 70%of90 days to42%of84 (including thoughts, intensity andfrequency), self-reported Significant reduction inmethamphetaminecravings Summary adherence totreatment (numberinfusions, pillcount). drug screens; self-report methamphetamine use (TLFB); Methamphetamine craving (visual analogue scale);urine Measures

participants improved over thetrial.There wasathree- RCT controlled placebo- double-blind, Level II— trial open-label Level IV– evidence Level of events. numbers adverse group, andlarge in thetreatment rate, especially but highdrop-out Adequate sample double-blind RCT. and conducted well-designed A high-quality, 2011. Urschel etal., as pilotfor open-label study Well-conducted assessment Quality

95 Appendix: Summary tables Summary Appendix: 96 Medication treatment options for amphetamine-type stimulant users eeec Medicine Reference America United Statesof 25(2): 254–262. pharmacology Journal ofPsycho mine dependence. methylampheta- initial treatment of gabapentin for flumazenil and controlled trialof et al.(2011). A Urschel, H.C. , gabapentin and Flumazenil of participants Number anddescription treatment; 88%placebo 30 days before: 89% Self-reported frequency not reported Mean use inlast30days: 21 years Age starteddrugs: approx. not reported methamphetamine use: Mean years of Mean age:notreported Males n=67(49%) previous three days methamphetamine within users whohadused methamphetamine 135 dependent nevninadcmaio frlvn Primaryoutcomesincludingmeasures used Intervention andcomparison ifrelevant day (US$50voucher forfoodorgasoline). if theycompletedtheirappointedvisits +1 protocol, participantsreceived incentives support. To encourage adherence to psychosocial intervention andnutritional All participantsreceived MatrixModel formulations ofthemedications (n=67). Placebo control group received inactive pre-infusion andPRNforsleep (n=68). 2 Active treatment group received flumazenil, 1200 1, 2,3,21 &22,oral gabapentinupto

mg administered intravenously ondays

mg/day andhydroxyzine 50

mg for and increase engagementinpsychosocial treatment. an optionforclinicians seekingtoreduce patientcraving reactions. Authors suggestthatthesemedications mayoffer (compared to21% intheplacebogroup) hadinjectionsite of whichwere mild.Closetohalfinthetreatment group of theplacebogroup experiencedadverse event, most(97%) trial. Seventy-four percentofthetreatment group and79% frequency ofuse increased inbothgroups throughout the group thantheplacebogroup ateachtimepoint,the frequency ofuse wassignificantlylowerinthetreatment methamphetamine screening inanITTanalysis. Although treatment group butthis wasnotsupportedby urine methamphetamine use wassignificantly reduced inthe demonstrated atday6ofa30-daytrial.Self-reported dependent participants, withthegreatest effect and gabapentininreducing craving inmethamphetamine- Results showed aneffectforacombinationofflumazenil Summary use andcorrelates ofself-report; adverse events. (TLFB); urinedrugscreens asindicesofmethamphetamine four categoricalscales);self-report methamphetamineuse Methamphetamine craving (sixvisual analoguescalesand Measures evidence Level of Level RCT controlled placebo- double-blind,

— assessment Quality reported. drop-out rate not sample but RCT withsizeable and designed Well-conducted

97 Appendix: Summary tables Summary Appendix: 98 Medication treatment options for amphetamine-type stimulant users Medicines nototherwise specified America United Statesof 11(1): 1–14. pharmacology ondan and efficacyof study ofthesafety of Neuropsycho national Journal dependence. Inter- methamphetamine the treatment of placebo- double-blind, nary randomized, (2008). Aprelimi- Johnson, B.A. etal. Reference America United Statesof Hollywood, Florida. Drug Dependence, on Problems of of theCollege Scientific Meeting 73rd Annual presented atthe pilot study. Paper dependence: a methamphetamine for thetreatment of (2011). Varenicline Swanson, A.etal. setron in contr olled , Medicine Varenicline Ondansetron of Number anddescription and matchedplacebo(n=46) or 4 0.25 Randomised toondansetron 11.7 Mean use inlastmonth: use: 18.4 years Mean years of methamphetamine Mean age:36years Males n=96(64%) methamphetamine users 150 dependent abstract. were reported inthis conference No otherparticipantlevel data users 20 dependent methamphetamine

participants

mg (n=38)orally twicedaily days mg (n=37),1

mg (n=29), if Intervention andcomparison 4 ondansetron 0.25 Participants were given Varenicline 1 week from weeks 1–8 group sessions, three timesper relapse prevention 90-min. All participants:CBT-based matched placebo(n=46). therapy using cognitive behaviour Weekly individualcounselling placebo foreightweeks

mg orally twicedaily(bid)or relevant

mg twicedailyor

mg, 1

mg, or compared with two of the three ondansetron treatment groups. adverse events were more likely to be reported in the placebo group ple comparisons, it was NS. Ondansetron was well tolerated, and compared with placebo (p=0.04) but after correction for multi- cantly less negative for the ondansetron (0.25 mg b.i.d.) group retention rates. The average decline in the drug score was signifi- (MAWQ) or in the rate of change in craving. No differences in clinical severity of methamphetamine dependence or withdrawal signifi of at least three consecutive weeks of abstinence. No statistically days, or rates of success vs failure in self-reported achievement methamphetamine level, self-reported non-methamphetamine-use There were no significant differences in drug use measures, urine Summary Questionnaire (MAWQ) created for the study; study retention. observer (CGI–O) and self (CGI–S); Methamphetamine Withdrawal Brief abstinence; ASI–Lite; Hamilton Depression Rating Scale (HAM–D); success vs failure at achieving at least three consecutive weeks of urine methamphetamine level; Substance Use Report (SUR); Weekly proportion of methamphetamine-free urine samples; fewer methamphetamine-negative urine drug screens. smoking status was found in GEE indicating that smokers provided in reducing methamphetamine use was observed. A main effect of adverse events. No statistically significant main effect for varenicline Primary outcomesincludingmeasures used Measures with respect tochangesindepression, craving, orinreported There were nosignificantdifferences betweentreatment groups methamphetamine-negative urinedrugscreens (9.6%vs31%). of abstinence(3.7vs12days) andgreater meanproportion of completion (10% vs60%)withtrends toward more meandays by days retained inthetrial(p=0.009;21 vs43days) andstudy The varenicline group hadhigherrates ofretention asmeasured Summary of medication. Urine screens formethamphetaminemetabolites;adverse events Measures

S c ubstance Craving Scale (BSCS); Clinical Global Impression — ant differences among the study groups in the scales of RCT controlled placebo- double-blind, Level II— trial (pilot) controlled placebo- double-blind Level II— evidence Level of rates. low retention sample sizebut RCT. Adequate well-conducted High-quality and research group. conducted by this currently being scale RCTis Note: Alarger abstract). (conference Briefly reported assessment Quality

99 Appendix: Summary tables Summary Appendix: 100 Medication treatment options for amphetamine-type stimulant users America United Statesof Scottsdale, Arizona. Drug Dependence, on Problems of of theCollege the AnnualMeeting Paper presented at preliminary analysis. outpatient trial: a controlled dependence, methamphetamine treatment of (2001). Amlodipine Batki, S.L.etal. Reference America United Statesof 177–184. Dependence, 85(3): Drug andAlcohol dependence. methamphetamine the treatment of and gabapentinfor trial ofbaclofen placebo-controlled Randomized, et al.(2006). Heinzerling, K.G. Amlodipine Medicine gabapentin and Baclofen of Number anddescription and AML10 (n=26), AML5 Randomly assignedtoPLA approx. Mean use inlast30days: 1.5 methamphetamine use: 8years Mean years of Mean age:35.6years Males n=59(77%) users 77 dependent methamphetamine (n=37) gabapentin (n=26)andplacebo Randomised tobaclofen(n=25), 15 days Mean use inlastmonth:approx. methamphetamine use: 9.5years Mean years of Mean age:32years Males n=61 (69%) users 88 dependent methamphetamine

participants

mg/day (n=26)

mg/day (n=25),

g prevention group sessions. of thrice-weekly, 90-min. relapse counselling program, consisting manual-driven psychosocial All participants received a standard if Intervention andcomparison placebo amlodipine 10 decreased to400 week 16whenthedosewas followed by 800 for days 1–3ofthefirst week Baclofen 10 given amlodipine5 Parallel outpatientgroups were medication inblister packages. dispensed aone-weeksupplyof of thestudyphysician, then was takenundersupervision blister packages. First dose Medication wasdispensed in last three days. Or gabapentin400 the lastthree days. was decreased to10 tid untilweek16whenthedose first weekfollowed by 20 day (tid)fordays 1–3ofthe

relevant

mg three timesper

mg perday, or

mg tiduntil

mg tidforthe

mg tid mg, or

mg tidfor

mg craving agent for methamphetamine-dependent individuals. but the short half-life of baclofen may limit its use as an anti- baclofen may have a small treatment effect relative to placebo, to be effective in treating methamphetamine dependence while groups. The authors concluded that gabapentin does not appear sample during the treatment period, but no difference between a higher probability of providing a methamphetamine-free urine baseline methamphetamine use were significantly associated with at counselling sessions, lower depression symptoms and less severe medication taken or psychosocial sessions attended. Attendance reductions in use compared to placebo. No differences in a higher percentage of study medication showed significant baclofen, but not gabapentin, participants who reported taking in reducing methamphetamine use, craving or retention. For There were no significant main effects for baclofen or gabapentin Summary analogue scale;pillcountformedicationadherence. methamphetamine craving measured weeklyusing avisual family/social, andpsychiatric; BeckDepression Inventory (BDI); functioning: medical,employment, druguse, alcoholuse, legal, the severity ofaddiction-related problems inseven areas of Urine samples collectedthree timesaweek;ASI–Litetomeasure Measures Primary outcomesincludingmeasures used dependence. ineffective intheoutpatienttreatment of methamphetamine The authors concludedthatamlodipinetreatment maybe dollar value), craving, qualityofhigh,or general functioning. No difference inretention, methamphetamine use (amount, Summary craving. Depression (BDI);retention; methamphetamine use ingrams; Measures trial controlled placebo- double-blind RCT controlled placebo- double-blind, Level II— evidence Level of randomised Level II— abstract). (conference Briefly reported completion). placebo 40% completion, and gabapentin 35% 60% completion, variable (baclofen out highand study, but drop- A well-conducted assessment Quality

101 Appendix: Summary tables Summary Appendix: 102 Medication treatment options for amphetamine-type stimulant users Comorbidity Reference United States of America United Kingdom 16(4): 373–377. Psychopharmacology, dependence. Journalof and amphetamine schizophrenia to patientswith dexamphetamine prescription of al. (2002).The Carnwath, T. et America United Statesof 143(1–3): 257–260. of AffectiveDisorders, dependence. Journal methamphetamine depression and bipolar andunipolar trial ofciticolinefor placebo-controlled double-blind, A randomized, Gabrielson, B. (2012). Brown, E.S.& 19(2): 190–191. Journal on Addictions abuse. methamphetamine with comorbid bipolar depression (2010). Modafinil for Camacho, A. et al. American , Medicine divalproex quetiapine, Modafinil, phetamine Dexam- Citicoline 34 years; 7female,13male Control 20participantsmeanage: 41.6 years; 15female,13male Citicoline group (n=28)meanage: initial assignment) analysis (12dropped outafter 48 participantsincludedinITT in last four weeks depression; methamphetamine use currently depressed or with major diagnosed with bipolar I, II or NOS, outpatients aged 18–70 years, 60 amphetamine-dependent participants Number anddescriptionof methamphetamine family functioning,craving for self-reported depression, poor methamphetamine use. Patient bipolar mixed typeand 38-year-old femalewith use schizophrenia andamphetamine Eight menaged23–46years with increasing to 1000 appearance for12weeks with placeboofidentical day atweek6,compared at week4,and2000 in week2,1500 Citicoline 500 oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and up to600 with afurtherincrease Modafinil 200 divalproex 1000 800 600 stabilised onmodafinil a three-month period, – 80 in therange of20 appropriate. Starting doses if considered clinically adjusted upwards only one-half this dose,and started atapproximately level of5%purity, usually assuming theusual local street amphetamineused, ing theestimateddoseof dose calculatedby match- Dexamphetamine daily—

mg atnight,and mg/day, quetiapine

mg/day

mg/day over

mg/day mg/day

mg/ differences incognitive outcomesordruguse were found. symptoms, andlongerstudysurvival thanplacebo.No Citicoline wasassociatedwithanimprovement indepressive Summary Test (HVLT)); anddruguse assessedby urinedrugscreens. Version —IDS–C);cognition(Hopkins AuditoryVerbal Learning Mood (Inventory ofDepressive Symptomatology:Clinician Measures of abstinence. in her cravings for methamphetamine and achieved six months and help with chores around the house. She described a decrease support improved. She was able to live again with her mother without subsequent induction of manic symptoms. Her family Patient reported a reduction in fatigue and depressive symptoms Summary No formalmeasures were used. Descriptive clinicalopiniononly. Measures improvement oneitherdomain. in bothsymptoms anduse, andtwopatients showed no significantly reduced use), twopatients hadsomeimprovement health andamphetamineuse (three patients abstinentandone group. Four patientshadgoodoutcomesforbothmental Dexamphetamine didnotexacerbate psychosis amongthis Summary monthly. unspecified psychiatric assessments were undertakenatleast Urine drugscreens; regular visual observation ofinjectingsites; Measures RCT controlled placebo- double-blind Level II— vdneQualityassessment evidence Level of one patient case studyof Level IV— patients of eight case study Level IV— ++ acceptable limits. drop-out within sample sizeand with reasonable conducted study Well-designed and – High risk ofbias. with singlecase. Low-level study _ of bias. treatment. Highrisk application of size andvariable with small sample Low-level study

103 Appendix: Summary tables Summary Appendix: 104 Medication treatment options for amphetamine-type stimulant users Reference America United Statesof 154(8): 1170. Journal ofPsychiatry, psychosis. American methamphetamine treatment of (1997). Risperidone Misra, L.&Kofoed, L. Malaysia 22(2): 121–129. Psychopharmacology, Bulletin ofClinical induced psychosis. for methamphetamine study ofaripiprazole (2012). Anopen-label Sulaiman, A.H.etal. Medicine iprdn A45-year-old Caucasianman Risperidone rppaoe49dependentmethamphetamine Aripiprazole participants Number anddescriptionof hallucinations. when hereported theonset of four months before admission, no psychiatric symptoms until the past5years. There hadbeen and hadincreased his use during methamphetamine 12years earlier who hadbecomedependenton income) (approximately 40%ofmean days: RinggitMalaysia 1,386.1 methamphetamine use inlast30 Mean amountspent on use: 5.6years Mean years ofmethamphetamine Mean age:34.2years Males n=46(93.9%) users with psychosis, 62% smoking oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and per day Risperidone 1 to day14. (5–15 followed by flexibledoses of 5–10 treated with an initial dose Eligible patientswere

mg/day) from day2

mg aripiprazole

mg twice increased to1.5 attention, insight andjudgmentimproved. Afterthedosewas organisation ofthought,delusional beliefs, memory, delusions andparanoia. Afteroneweekmood,affect, Within three days thepatientnotedreduced hallucinations, Summary No formalmeasures were used. Descriptive clinicalopiniononly. Measures ceased. Insomnia, impulsivity, andanhedoniaalso improved. hallucinations andcraving formethamphetaminepromptly Upon resumption ofrisperidone treatment oneweeklater, his He also resumed smoking andcraved methamphetamine. taking risperidone, andhis auditoryhallucinations recurred. and delusions ceased.Two weeks intotreatment hestopped noted withrespect tomovement-related adverse events. in 10 (20.4%)patients. Nostatistically significantchanges were well tolerated duringthestudy. Adverse events were reported score and2.0±1.2pointforCGI–S.Aripiprazole wasgenerally was 27.6±21.4 pointfrom baselineonday14fortotalPANSS CGI–S scores over thecourse ofthestudy. Themeanreduction There wasasignificantdeclineinthemeanPANSS-total and Out of49patientsenrolled, 41 (83.7%)completedthestudy. Summary Anxiety Depressions Scale(HADS). Scale (SAS);ClinicalGlobalImpression Scale(CGI–S);Hospital Scale (AIMS);BarnesAkathisia Scale(BARS);SimpsonAngus Symptoms Scale(PANSS);AbnormalInvoluntary Movements Brief SubstanceCraving Scale(BSCS);Positive andNegative MINI; AmphetamineWithdrawal Questionnaire (AWQ); Measures

mg twicedailytheauditoryhallucinations vdneQualityassessment evidence Level of one patient case studyof Level IV— group a control without clinical trial open-label Level IV— – High risk ofbias. with singlecase. Low-level study rates. but highretention 14-day follow-up duration withonly group; ofvery short with nocontrol open-label study Well-conducted

105 Appendix: Summary tables Summary Appendix: 106 Medication treatment options for amphetamine-type stimulant users Reference America United Statesof 69(8): 1257–1266. Clinical Psychiatry, blind trial.Journalof randomized, double- dependence? A disorder andstimulant co-occurring bipolar effectively treat antipsychotics (2008). Doatypical Nejtek, V.A. etal. America United Statesof 159(11): 1947–1948. Journal ofPsychiatry, dependence. American and amphetamine for socialphobia M.B. (2002).Modafinil Camacho, A.&Stein, America United Statesof 2009(1): CD003026. Systematic Reviews, Database of psychosis. Cochrane for amphetamine (2009). Treatment Shoptaw, S.etal. Medicine quetiapine and Risperidone oaii 45-year-old Caucasian woman, Modafinil haloperidol and Olanzapine participants Number anddescriptionof or quetiapine(n=48)) Randomised torisperidone (n=46) Mean age:35.7years Males n=44(47%) mixed symptoms current manic,hypomanicor diagnosis ofbipolardisorder with methamphetamine users with 80 dependentcocaineor age 28years dependent onamphetaminesince (2005) below) participants (Leelahanajetal. controlled trialinvolving 58 A review ofonerandomised oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and by week12. risperidone was0.5 Weekly dosingfor 12 weeks week, andupto6 1 day forthefirst week, and upto600 day forthesecondweek, for the first week, 100 quetiapine was50 Weekly dosingof conditions. groups underblinded randomly assignedtotwo Study medications were weekly visits for20weeks. Participants attendedfor 200 fluoxetine twice daily, 40 compared tohaloperidol One studyofolanzapine

mg/day forthesecond

mg modafinil

mg/day mg/day by

mg/day mg/day

mg/

mg/ craving ordruguse. significantly differintheireffectsonmoodsymptoms, drug less frequent druguse (p=.03).Thetwomedications didnot compared tobaseline.Decreased drugcravings were related to and depressive symptoms andreduced drugcravings (p<.0005) (n=42) andrisperidone (n=38)significantlyimproved manic mg/day and3.1±1.2forrisperidone. Bothquetiapine The mean±SDexitdoseforquetiapinewas303.6151.9 baseline andatleastonefollow-upstudyvisit wasavailable. medication, anevaluable sample of80patientswhoattended intention totreat sample thatreceived oneweekofstudy Of 124consenting outpatientsand94participantsinthe Summary complaints. PRD–III indicategreater severity ofmood,cravings andsomatic complaints. Higherscores ontheYMRS,IDS–C-30,SCQ-10 and 10 –measures moodanddrugcraving; PRD–III–somatic YMRS –11 items; IDS–C-30–30-itemdepression scale;SCQ- Measures with modafinil that she experienced with amphetamine. employment, and she reported not experiencing the same ‘high’ of time looking for street amphetamine so was able to obtain in depression and anxiety. Reported she no longer spent a lot Self-reported decrease in craving for amphetamine, improvement Summary symptoms. Self-reported amphetaminecraving, depression andanxiety Measures symptoms thanparticipants takinghaloperidol. olanzapine hadsignificantly fewerextrapyramidal side-effect treating amphetamine-induced psychosis. Participants taking haloperidol administered attherapeutic doseswere effective in antipsychotic olanzapineandtheolder, typicalantipsychotic Results from asinglestudyshowed that boththeatypical Summary vdneQualityassessment evidence Level of trial randomised double-blind Level II— one patient case studyof Level IV— review systematic Level I– placebo control. group RCTwithno out rate andtwo with highdrop- Good-quality study of modafinil. clinical application editor aboutthe Brief lettertothe Cochrane review. High-quality

107 Appendix: Summary tables Summary Appendix: 108 Medication treatment options for amphetamine-type stimulant users Reference America United Statesof 20(3): 393–394. Psychopharmacology, of Clinical psychosis. Journal of methamphetamine Olanzapine treatment Misra, I.etal.(2000). Thailand Thailand, 88(3): 43–52. Association of of theMedical psychosis. Journal of amphetamine in thetreatment with haloperidol of olanzapine blind comparison 4-week, double- et al.(2005).A Leelahanaj, T. Medicine lnaieMaleaged50years withhistory Olanzapine haloperidol and Olanzapine participants Number anddescriptionof use. one year ofmethamphetamine paranoid-hallucinatory stateafter dependency. Developed persistent of alcohol,cannabis andcocaine or haloperidol(n=29) Randomised toolanzapine(n=29) in pastmonth. of substance abuse or dependence other psychotic disorder, diagnosis diagnosis ofschizophrenia or Exclusion criteriaincluded 4.5 years Mean years ofamphetamineuse: Mean age:22.7years Men n=54(93%) 36 orhigher Psychiatric RatingScale(BPRS)of a baselinescore ontheBrief smokers ofamphetaminewith amphetamine psychosis. Allwere 58 participantswithDSM–IV oprsni eeatPrimaryoutcomesincludingmeasures used comparison ifrelevant Intervention and twice daily) later increased (to5 olanzapine (5 outpatient trialof Patient wasgiven an 4 Trihexyphenidyl upto behaviour waspermitted. agitation orviolent benzodiazepine forsevere Limited use of double-blind period. during thefour-week range of5–20 within thealloweddose increments ordecrements be adjusted in5 the studydrugcould each seven-day period, the studydrug.After effects waspermitted. treat extrapyramidal side with 5–10 outpatients andstarted All participantstreated as

mg/day for<2days to

mg/day of

mg/day), mg/day

mg 65.5%, (x2=6.73,df=1,p=0.01)). have completedtreatment thanthehaloperidolgroup (n=19, olanzapine group (n=27,93%)were significantlymore likelyto patients completedthestudythandidhaloperidolpatients. The more weightgainthanhaloperidolpatients. More olanzapine olanzapine patients. Butolanzapinepatientsexperienced due toextrapyramidal sideeffectscompared tononeofthe One-third ofthehaloperidolpatientsdiscontinued treatment psychosis, withatleast40%improvement inthefirst week. Both medications were effective intreating symptoms of Summary Scale (CGI); adverse events; medication safety profile (SAS & BAS). methamphetamine-induced psychosis. be effective inthetreatment ofacuteandresidual The authors suggestthatatypicalantipsychotics can eliminated his psychotic symptoms. dose andabstinencefrom methamphetaminesubsequently occasionally using methamphetamine.Anincreased olanzapine but headmittedtomissing several olanzapinedosesandto Within twoweeks, his acutepsychotic symptoms were reduced, methamphetamine-dependent patient. effectively treated bothacuteandresidual psychotic statesofa The authors report thatolanzapineon two separate occasions Summary No formalmeasures were used. Descriptive clinicalopiniononly. Measures Brief Psychiatric RatingScale(BPRS);ClinicalGlobalImpression Measures trial randomised double-blind Level II— vdneQualityassessment evidence Level of one patient case studyof Level IV— No placebocontrol. high-quality study. Well-conducted, measures. few systematic case report with Low-level single

109 Appendix: Summary tables Summary Appendix: 110 Medication treatment options for amphetamine-type stimulant users Other amphetamine-typestimulants MDMA Reports Letter]. low-dose aripiprazole. [Case following treatment with ephedrine dependence of a 20-year history of and selective remission (2007). A case of unexpected Arnold, K.K. & Yager, J. Reference Iran 601–602. Pharmacology, 19(5): Fundamentals ofClinical consumption: acasereport. Topiramate prevents ecstasy Hampa, A.D.(2005). Akhondzadeh, S.& Reference United StatesofAmerica 1620–1621. Clinical Psychiatry United StatesofAmerica Addictions, 14(3):300–301. American Journalon induced depression. Mirtazapine forMDMA- Fetter, J.C.(2005). Journal of , 68(10): aripiprazole plus Fluoxetine Medicine 28-year-old female used Mirtazapine 28-year-old male Topiramate Medicine (forgery) shopping, illegalactivity disorder, compulsive depression, eating weight, history ofmajor 20 years tomaintain using ephedrinefor 37-year-old female, of participants Number anddescription the start of MDMA use. patient said was linked to and anxiety, which the years, with depression year. Abstinent for six MDMA weekly for one provided. of use. Nootherdetails alcohol) andlonghistory dependence (opiatesand 4 years; multipledrug 2–4 timesperweekfor patient used MDMA of participants Number anddescription panic attacks titrated upto200 the first day, whichwas aripiprazole and 2.5 80 mg/dayfluoxetine Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and 25 nightly; hydroxyzine Mirtazapine 30 dose forthree months. week. Hewasonthis day duringthesecond 50 Primaryoutcomesincludingmeasures used comparison ifrelevant Intervention and

mg asneededfor mg oftopiramate on

mg/day

mg/ clinical applicationfordependence. content/81/6/2611.full)), sotheseresults are unlikelytohave equivalent toabout48 only and the patient was followed up for three months only. euphoria in this single case study, but consumption was self-report topiramate 200 mg/day appears to have prevented MDMA-induced for the 12-week follow-up period’. Authors conclude that 4 to 1 per day, sleep improved and ‘symptom remission continued Patient reported feeling ‘pretty good’, panic attacks decreased from Summary Self-reported symptoms ofdepression, anxietyandsleep. Measures dose ofpseudoephedrinedailyforcoldandflu is 120 daily, whichis avery small dose(e.g.the recommended The casereports onapatientwhowasusing 1.5 Remained ephedrine-free forthefollowingfour months. Patient tapered herself offephedrineover aperiodofeightweeks. Summary use MDMAinfuture. and reported noeuphoriceffectsandstatedhefeltdesire to Patient reported using MDMAonceduringthetreatment period Summary Self-report MDMAconsumption. Noformalmeasures were used. Measures

mg ofephedrine(seejap.physiology.org/

mg ephedrine

mg, study single case Level IV— study single case Level IV— study single case Level IV— vdneQualityassessment evidence Level of Qualityassessment evidence Level of relevance. of minorclinical Low-level study follow-up period. measures andshort outcomes, noformal with poorlyreported Low-level study follow-up period. measures andshort outcomes, noformal with poorlyreported Low-level study

111 Appendix: Summary tables Summary Appendix: