Atoda.org.au
options foroptions for
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 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.
About the authors
Nicole Lee is a practising psychologist, Associate Professor at the National Centre for Education
and Training on Addiction at Flinders University, and holds adjunct appointments at Curtin
and Monash universities. With Linda Jenner, she is co-director of LeeJenn Health Consultants.
She has served on the boards of the Australasian Professional Society on Alcohol and other
Drugs and the Alcohol and other Drugs Council of Australia, and was the Queensland, Victorian
and National President of the Australian Association for Cognitive and Behaviour Therapy.
Linda Jenner is a registered nurse and holds a Masters in Applied Science (Research). She has worked as a clinician, researcher, educator and consultant in the alcohol and other drugs and mental health fields since 1978. Prior to LeeJenn Health Consultants, she was a Senior Research Fellow in Clinical Research at Turning Point Alcohol and Drug Centre and wrote clinical guidelines, delivered training, and developed and evaluated treatment programs.
Dr Suzanne Nielsen is an Early Career Research Fellow with the National Health and Medical Research Council, based at the University of Sydney. She recently completed a National Institute on Drug Abuse (NIDA) Clinical Trials Network INVEST Fel owship at UCLA Integrated Substance Abuse Programs focusing on a national multi-site clinical trial examining buprenorphine in the presence of naltrexone for cocaine dependence. Previously she worked as a pharmacist and Senior Research Fellow at Turning Point Alcohol and Drug Centre.
LeeJenn Health Consultants website: <www.leejenn.com.au>.
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: • Adrian Dunlop • Margaret Hamilton • Nick Lintzeris • Steven Shoptaw Tables and figures
Executive summary
Background
Australia has one of the highest rates of amphetamine-type stimulant (ATS) use in the world.
Around 2.5 per cent of people over the age of 14 years have used ATS in the past year, and
estimates suggest more than 72 000 may be dependent users.
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 effects of these actions manifest differently among people who use ATS during intoxication (e.g. euphoria, increased energy, confidence) and withdrawal (e.g. low mood, agitation, irrit-ability), making the identification of effective pharmaceutical agents a complex endeavour.
Regular long-term use of ATS can result in dependence, especially in those who use by injection or smoking. On cessation, dependent users can experience a range of withdrawal symptoms such as insomnia, irritability, dysphoria, depression and lack of motivation, while strong craving to use is also a common feature.
Neurotoxicity is associated with chronic and long-term exposure to ATS, with imaging studies demonstrating significant dopamine transporter reductions in the brains of methamphetamine 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), commonly known as ecstasy. As a consequence, ATS users often experience problems with concentration and memory, impaired decision making, irritability, insomnia, mood swings, loss of interest in pleasurable activities, and lack of motivation.
ATS users are notoriously difficult to attract and retain in treatment, with less than 20 per cent of dependent users entering treatment. Many users attempt to withdraw from ATS without specialist supervision, and the use of other illicit drugs to self-manage the symptoms of withdrawal is common. ATS users tend to seek formal treatment only when the consequences of ATS use are severe and typically when abstinence is the treatment goal. Clinicians and researchers have called for more research into effective pharmacotherapies for this group to broaden treatment options and attract more ATS users into treatment.
In recent years, considerable attention has been focused on developing effective psychosocial interventions for ATS users and psychological interventions are currently the treatment of choice. Yet, despite the effectiveness of psychosocial approaches, treatment attrition and subsequent relapse rates are high, prompting strong interest in pharmacological treatments. Even with considerable research efforts, so far no medications have demonstrated sufficient effectiveness to warrant widespread approval in Australia or internationally for the treatment of ATS dependence or withdrawal, leaving an important gap in evidence-based treatment options for health workers and their clients. There is a broad range of views about the use of pharmacotherapy within the alcohol and other drug treatment sector more generally, and specifically for ATS treatment.
Purpose of this review This review was designed to examine, in greater detail than previous reviews, whether there are medicines that show promise in forming part of a comprehensive treatment plan, and conversely whether there are medicines that are unsafe to use with people who are depend- s for amphetamine-type stimulant u ent on ATS. Both statistical and clinical significance was considered in the review, and an in-depth meta-narrative analysis of identified studies was undertaken.
This review of the evidence for pharmacotherapies for ATS treatment articulates the potential role for medicines in the treatment of ATS dependence and related conditions, including which medicines show potential. The review is also designed to help to guide discussion related to the next steps, including the development and updating of clinical guidelines, and identification of areas for concentration of future research efforts in Australia.
A systematic review method, coupled with a modified meta-narrative approach to the inter-pretation of findings, was undertaken. Systematic reviews use a thorough, systematic search method as their primary vehicle and can include any type of study (including qualitative and case studies). They differ from a general review in that the search method and the evaluation of the articles are explicit and replicable. A newer form of review has emerged to help researchers interpret the literature when methods, measures and outcomes vary widely. Rather than presenting and interpreting the evidence as ‘all-or-nothing' (that is, whether the weight of the evidence is for or against the use of a medicine), meta-narrative review is designed to examine similarities and differences in the data and to look beyond ‘what' to ‘why', ‘how', ‘for whom' and ‘in what circumstances'.
The databases searched were MEDLINE, PsycINFO, Embase and the Cochrane Database of Systematic Reviews. The search period was January 1997 to January 2013. Hand-searching of specific papers also identified some additional studies.
Included papers were human studies, studies of adult participants, articles published between 1997 and 2013 (last 15 years), manuscripts in English or with available English translation, and at least Level IV methodology (according to the National Health and Medical Research Council levels of evidence). Excluded were animal studies, non-English manuscripts, studies published prior to 1997, qualitative studies, general reviews, studies that included primarily non-dependent participants, studies that included primarily non-treatment participants or contexts (e.g. used healthy volunteers or used dependent volunteers in a laboratory setting), and studies of pharmacotherapy responses to acute toxicity.
Withdrawal from amphetamines
Twelve separate studies that reported the effects of medicines on any symptom of ATS
withdrawal were reviewed. The evidence was inconclusive but, despite small sample sizes,
some positive results were found. Where medicines showed non-significant effects compared
to placebo, in general participants in both groups improved.
There was no evidence found for the use of benzodiazepines or other medicines for the management of sleep disturbance or agitation among ATS users in withdrawal, even though these medicines are commonly recommended in clinical guidelines.
Of the four medicines that have been studied for withdrawal from amphetamines, modafinil, mirtazapine and dexamphetamine appear to offer some benefits during ATS withdrawal and may also assist with relapse prevention. The fourth medicine, amineptine, is not available in Australia. Modafinil is thought to act on the dopamine transporter, while mirtazapine is known to enhance noradrenergic and serotonergic transmission. Dexamphetamine and amineptine both work by increasing levels of monoamines at the synaptic cleft.
The evidence from this review, although limited, suggests that modafinil, mirtazapine and dexamphetamine may have a potential role in the range of symptom-management strategies available for methamphetamine withdrawal, and merit further investigation. Future clinical guidelines should detail the circumstances under which these medicines could be used, and for whom, and the medical monitoring strategies that would ensure their safe use.
• 60 mg of mirtazapine demonstrated effectiveness in reducing withdrawal symptoms in some participants over a 14-day period; lower doses did not produce convincing effects • 400 mg of modafinil demonstrated effectiveness, when tolerated by patients, in reducing withdrawal symptoms in some participants over a 7–10 day period; lower doses did not produce convincing effects • 60–110 mg of dexamphetamine demonstrated effectiveness in reducing withdrawal symp- toms in some participants over a 2–8 week period • although 300 mg of amineptine demonstrated effectiveness in some studies, there is some question about its abuse potential and it is currently unavailable in Australia.
There were no serious adverse events reported in the 12 studies reviewed, but given the small number of studies and the lack of strong evidence either for or against the routine use of these medicines as pharmacotherapy for ATS withdrawal, further research is required to inform the development of clinical guidelines.
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 and there is a high relapse rate during and after ATS withdrawal. Further research is warranted to confirm the effectiveness of these medicines.
Treatment for amphetamine dependence
Thirty-nine studies were identified, examining 18 potential pharmacotherapies, though each
has been the subject of relatively few studies at the time of writing. Dexamphetamine has
been the subject of the greatest number of studies (seven), including four randomised con-
s for amphetamine-type stimulant u trolled trials (RCTs); followed by modafinil (five) including three RCTs; and bupropion (four), all RCTs. The evidence is sparse for the remainder.
No medicine demonstrated consistent evidence of effectiveness in reducing ATS use or preventing relapse among dependent methamphetamine users. All of the studies conducted to date are smaller-scale feasibility studies. Larger RCTs are required to enable results to be generalised to the broader population of ATS users in Australia and to be interpreted with confidence.
The fol owing medicines were reported to be reasonably wel tolerated by research participants and showed some benefit in the studies reviewed: • Dexamphetamine was found to reduce the severity of ATS dependence and increase treatment retention. The most effective dose was 100 mg per day taken in the morning to limit sleep disturbance.
• Modafinil was found to be superior to placebo in reducing ATS use among those who were medicine-compliant. The most effective dose was 400 mg per day taken in the morning to limit sleep disturbance.
• Bupropion was effective in reducing ATS use by ‘lighter' ATS users (<18 days use per month) and men. The most effective dose was a starting dose of 150 mg per day increas-ing to 300 mg per day after three days taken either in the morning or in divided doses (150 mg morning and 150 mg evening).
• Naltrexone may improve retention in treatment and reduce craving. The most effective dose was 50 mg per day (optimal time for daily dosing was unspecified).
• Methylphenidate may improve retention and reduce use. The most effective dose was a starting dose of 18 mg daily increasing to 36 mg daily in the second week, and 54 mg daily from week 3 onwards (optimal time for daily dosing was not specified).
Although these medicines appear to have been beneficial for some participants, they cannot be recommended for routine treatment of methamphetamine dependence due to insufficient evidence. These medicines require further research with large numbers of Australian partici-pants under local conditions of ATS use. Most of the studies reviewed were conducted over 8–12 weeks, so the effectiveness and safety of these medicines for long-term use are unknown.
A number of other medicines showed promise for the treatment of amphetamine depend-ence but as the number of studies is too small to draw conclusions, additional research is 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, psychosis, epilepsy and smoking cessation: • varenicline.
Other medicines showed either limited or no benefit, or an unacceptable adverse effect profile. They are not recommended for use or as a high priority for further study: • baclofen (limited evidence of benefit) • gabapentin (limited evidence of benefit) • ondansetron (limited evidence of benefit) • amlodipine (limited evidence of benefit) • aripiprazole (unacceptable adverse effect profile) • vigabatrin (unacceptable adverse effect profile) • sertraline (unacceptable adverse effect profile) • Prometa™ protocol of combination flumazenil and gabapentin (unacceptable adverse effect profile).
Overall, many studies were conducted on small numbers of participants and there were high drop-out rates and low medication adherence. Future research that examines ways to retain patients in pharmacotherapy treatment and to improve medication adherence may be useful.
The studies showed variable outcomes and some results were conflicting. Many had small sample sizes while poor participant retention and low adherence to prescribed pharmaco-therapy were common barriers to gaining high-quality results. Australians tend to use ATS in patterns that differ from users in other countries (e.g. high rates of injecting) and, as most of the evidence has been gained from international studies, research is needed to examine the effectiveness of medicines that show promise for treating ATS-dependent adults in Australia.
Other considerations in the treatment of amphetamine use Role of adherence to prescribed medicines
In most of the studies, adherence to taking medicines as prescribed was low. Many studies s for amphetamine-type stimulant u found a correlation between medication adherence and better outcomes, so careful monitoring of adherence is important for ensuring effectiveness of treatment. In some studies, attrition rates were very high, suggesting that helping clients maintain their motivation for treatment is also necessary for treatment success. Some clinicians argue that providing pharmaco-therapies in conjunction with psychosocial therapies will increase the number of ATS users who enter treatment, and the evidence suggests that medicines can increase the length of time they remain in treatment. The use of strategies such as contingency management (that is, a program of planned incentives for treatment goals met) to increase adherence to taking medicines as prescribed may also improve outcomes.
Role of psychosocial interventions
Nearly all of the studies reviewed utilised psychosocial interventions, some quite intensively, in conjunction with pharmacotherapy. Although rates of attendance at counselling sessions varied between studies, psychosocial interventions for both the treatment and placebo groups may have masked the effectiveness of the medicines.
Psychosocial interventions, such as the Matrix Model (Rawson et al., 1995), which is used extensively in the United States of America, and the Baker et al. (Baker et al., 2005) four-session brief cognitive behaviour therapy (CBT) intervention, which is offered widely in Australian treatment settings, have been shown to be effective among methamphetamine users.
Another complicating factor is that many of the studies employed intensive assessment procedures as part of their protocols. There is evidence to suggest that assessment itself is therapeutically beneficial (Kypri, Langley, Saunders & Cashell-Smith, 2007), which may have created a ceiling effect in some studies that is unlikely to be replicated in the clinical setting.
There is some emerging work on ‘third wave' CBT interventions for ATS users, such as accept-ance and commitment therapy (ACT), but these studies remain unpublished in the peer review literature, providing little guidance on whether these interventions are effective with ATS users on their own or in conjunction with medicines. Systematic reviews that have examined ACT have found it to be effective with other disorders, but no more effective than traditional CBT, and have noted that the quality of the research is relatively poor (e.g. Ost, 2008).
The majority of the studies were undertaken in the United States of America. This is an important consideration for Australia because the nature of methamphetamine use and the treatment systems in each country differ. Among Australians who use drugs by injection, approximately 70 per cent use ATS (Stafford & Burns, 2012) and studies from the United States rarely included injecting methamphetamine users. Care is needed in translating these results for an Australian clinical setting.
Subgroups of amphetamine users
Very little evidence is available about which particular medicines prescribed, under what conditions, might benefit subgroups of amphetamine users.
Elkashef et al. (2008) showed that, for the subgroup of participants who had ‘lighter' use of methamphetamine at baseline, bupropion treatment increased weekly periods of abstinence (56%) compared to placebo (40%), and less frequent users also showed a greater rate of decrease in urine quantitative methamphetamine than placebo. Shoptaw et al. (2008) also found that less frequent users were nearly three times more likely to have a methamphetamine- free week than heavier users during treatment with bupropion compared with placebo. Although bupropion did not show benefit overall, post-hoc analyses suggest that there may be some benefit for less frequent users (e.g. <18 days of use in the last 30 days).
Shearer et al. (2009) found poorer outcomes for HIV-positive participants taking modafinil and poorer outcomes for methamphetamine-dependent participants with comorbid opioid dependence compared to those with methamphetamine dependence only.
Gender differences in outcomes were rarely reported in the studies reviewed. However, Elkashef et al. (2008) reported that bupropion was associated with reduced methamphetamine use in men but not women.
Treatment of co-occurring mental health problems with
amphetamine dependence
The dominance of case studies, coupled with a lack of standard measures, makes it difficult to
draw specific conclusions about the effectiveness of these medicines for people with mental
health problems who use ATS. A range of medicines, including antipsychotics, dexampheta-
mine, modafinil and citicoline, were found to be safe in the studies reviewed and may be
effective for treatment of co-occurring mental health problems among methamphetamine
users if used within existing guidelines for the general population of people with mental
health disorders; but, given the lack of specific evidence, additional research is required.
Treatment of other amphetamine-type stimulant dependence
Other than methamphetamine, very few other ATS result in significantly problematic use.
Most of the problems associated with MDMA involve acute toxicity and it is rare for MDMA
to be associated with chronic heavy use.
Only two studies that examined the role of medicines for treating MDMA dependence were identified for this review and both were single-case designs. Overall, there was little evidence for the effectiveness of pharmacotherapy for MDMA treatment and, with the exceptions of symptomatic relief from withdrawal or co-occurring mental health symptoms, psychosocial intervention remains the treatment of choice for MDMA users.
Only one single-case design was identified that examined the role of medicines for treating ATS dependence other than methamphetamine and MDMA.
Given the very small numbers of dependent users of other ATS, research into pharmaco-therapies is likely to be more productive if focused on treating methamphetamine dependence.
Introduction
Amphetamine-type stimulant use in Australia
Amphetamine-type stimulants (ATS) include methamphetamine, MDMA and a range of other
synthesised analogues. Australia has one of the highest rates of ATS use in the world. In 2010,
2.5 per cent of people aged 14 years and over (about 400 000) had used methamphetamine
in the past year, with 6.8 per cent of 20–29 year olds reporting use in the previous year. In
2010, 3 per cent or 550 000 people aged 14 years and over had used ecstasy (3,4-methylene-
dioxymethamphetamine, MDMA) in the previous year, with the highest use among people
aged between 20 and 29 years (10%) (Australian Institute of Health and Welfare, 2011).
A 2011 report showed an increase in methamphetamine use among police detainees, with 21 per cent testing positive, up from 16 per cent in 2010 and 13 per cent in 2009 (Sweeney & Payne, 2012), compared to about 11 per cent of detainees who tested positive for heroin use (Australian Crime Commission, 2012) for which effective pharmacological therapies are widely available.
Primary mechanisms of action of amphetamine-type stimulants
Amphetamines and their analogues are complex drugs that have multiple mechanisms of
action in the brain, the effects of which manifest differently during intoxication and with-
drawal. The initial effects of ATS are mediated by neurotransmitter systems, primarily through the dopamine system but also through the serotonin and noradrenergic systems. Ampheta-mines and their structural analogues increase levels of monoamines1 (dopamine, noradrenaline and serotonin) through a number of mechanisms, including inhibiting re-uptake through various transporter systems, resulting in higher concentrations of monoamines at the synaptic cleft. Stimulant effects are also achieved by increasing release of monoamines, or inhibiting enzymes that break down monoamines (Rose & Grant, 2008).
The dopamine system is involved in movement, attention and memory, and purposeful behaviour. It is the primary pathway for reward, which is thought to influence the develop-ment and maintenance of drug dependence and cravings (Volkow, Fowler & Wang, 2002). Serotonin is involved in a variety of important activities including control of mood, appetite, sleeping, thinking, perception, physical movement, temperature and blood pressure regula-tion, pain control and sexual behaviour. Noradrenaline is primarily involved in the ‘fight or flight' response: it stimulates the central nervous system to increase heart function and blood circulation, concentration, attention, learning and memory.
Methamphetamine primarily affects the dopamine system, whereas MDMA primarily exerts its action on the serotonergic system (Majumder & White, 2012).
1 Monoamines are a particular class of neurotransmitter that have a single amine group in their Effects, consequences and harms of amphetamine-type
stimulants
The rapid release of neurotransmitters caused by ATS acts to boost energy, promote wakeful-
ness and reduce appetite. Users also report increased self-esteem and sociability, lowering of
s for amphetamine-type stimulant u inhibitions and heightened sexual arousal (Halkitis, Fischgrund & Parsons, 2005), all of which can last for around 8–10 hours due to the long half-life of ATS (Cruickshank & Dyer, 2009).
Short-term physiological consequences can include restlessness and agitation, teeth grinding, elevated blood pressure, rapid heartbeat and palpitations. Acute toxic effects of ATS include chest pain, tremors, dangerously high body temperature, muscle spasm, brain haemorrhage, heart attack and seizures.
Adverse psychological effects, such as anxiety, irritability and insomnia, can also occur, while many long-term users at some time can experience depression, paranoia and psychotic symptoms (McKetin, McLaren, Lubman & Hides, 2006).
Regular long-term use of ATS can result in dependence. Among a sample of regular metham-phetamine users in Sydney, McKetin and colleagues found the highest rates of dependence among injectors (62%) and smokers (53%), while 25 per cent of those who usually snorted or ingested methamphetamine were dependent (McKetin, Ross, Kelly & Baker, 2008). On cessation of ATS use, dependent users can experience a range of withdrawal symptoms, such as insomnia, irritability, dysphoria, depression and lack of motivation, while strong cravings to use also commonly feature in ATS withdrawal states (Jenner & Saunders, 2004).
Neurotoxicity is associated with chronic and long-term exposure to ATS, with imaging studies demonstrating significant dopamine transporter reductions in the brains of methamphetamine users up to one year following abstinence (Volkow et al., 2001). Serotonin is thought to be similarly depleted after chronic exposure, particularly in users of MDMA (Barr et al., 2006; Dean, 2004). As a consequence, ATS users often experience problems with concentration and memory, impaired decision making, irritability, insomnia, mood swings, loss of interest in pleasurable activities, and lack of motivation. Newly abstinent methamphetamine users have been found to perform significantly worse on the Stroop Test (a measure of a person's ability to direct his or her attention) when compared to those who had been abstinent for one year or more, suggesting that attentional focus and executive functioning require many months to recover, during which time impulsive behaviour may be difficult to control (Salo et al., 2009).
Psychosocial treatment for amphetamine-type stimulant users
For more than a decade, clinical researchers have highlighted the reluctance of ATS users
to enter treatment (Vincent et al., 1999). In 2005, for example, researchers estimated that
among the 100 000 Australians who used methamphetamine regularly, more than 72 000
were likely to be dependent (McKetin, McLaren, Kelly, Hall & Hickman, 2005), yet in the same
period there were fewer than 15 000 closed treatment episodes for which amphetamine was
the primary drug of concern (Australian Institute of Health and Welfare, 2013).
Many users attempt to withdraw from ATS without specialist supervision, and self-medication (using other illicit drugs) to manage the symptoms of withdrawal is common (Kenny, Harney, Lee & Pennay, 2011). ATS users tend to seek formal treatment only when the consequences of use are severe (Baker, Gowing, Lee & Proudfoot, 2004) and typically when abstinence is the ultimate goal (Kenny et al., 2011).
Considerable attention has been focused on developing effective psychosocial interventions for this group in recent years and structured psychological interventions are currently the treatment of choice. Contingency management, an approach that uses immediate reinforcers such as vouchers to reward drug-free behaviour, and cognitive behaviour therapy (CBT) have both demonstrated effectiveness in assisting ATS users to attain abstinence (Lee & Rawson, 2008). Psychological interventions also have the benefit of addressing co-occurring mental health problems among ATS users. One Australian study, for example, found that four sessions of CBT increased rates of abstinence and also significantly reduced the severity of depression among ATS users (Baker et al., 2005).
Other treatment options available to ATS users include residential rehabilitation, which was found to be associated with short-term reduction in methamphetamine use in about one-third of treatment completers, and detoxification, which was found to have similar outcomes to no treatment at all (McKetin et al., 2012) and should therefore be used only as a first step in a structured treatment program.
Despite the effectiveness of psychosocial approaches, treatment attrition and subsequent relapse rates are high, particularly among people with more severe dependence and longer duration of ATS use (Brecht, Greenwell & Anglin, 2005). Even when psychosocial interven-tions are tailored specifically for stimulant users, only about 40 per cent complete treatment (Rawson et al., 2004).
As pharmacotherapies such as methadone have been shown to increase retention in treat-ment of people dependent on opioids (Mattick, Breen, Kimber & Davoli, 2009), clinicians and researchers have called for more research into effective pharmacotherapies for ATS users to broaden treatment options and attract and retain more ATS users in treatment (Kenny et al., 2011; Pennay & Lee, 2009).
Medicines and their potential uses in amphetamine-type
stimulant treatment
The medicines that have been trialled in the reviewed studies target a wide range of under-
lying mechanisms of ATS dependence, including reward pathways and craving, psychiatric
s for amphetamine-type stimulant u vulnerabilities and common symptoms of withdrawal and dependence. The medicines achieve their effects through modulation of key neurotransmitter systems, primarily dopaminergic neurotransmitter systems, but also the serotonergic and gabaergic systems. For some medicines the exact mechanism of action is still unclear. Medicines known to improve cognition and those that target specific symptoms associated with ATS use, such as depression, have also been investigated. Unike cocaine, there has been no human trial of a vaccine for ampheta-mine dependence, though reports from recent animal studies show promise.
Functional agonist pharmacotherapies
Functional agonist pharmacotherapies possess properties similar to the target drug of concern. They work by binding to the same receptors in the central nervous system as the target drug and triggering a similar but moderated or less intense effect. In some cases, functional agonist medicines reduce the effect of the target drug if it is used concurrently, thereby limiting its rewarding effects.
Agonist medicines are currently used to treat opioid dependence (e.g. the opioid agonist methadone and the partial opioid agonist buprenorphine) and tobacco dependence (e.g. nicotine patches). They offer some advantages for dependent users in comparison to illicit drug use by delivering a known and measurable dose, a legal and regular supply, and reduced potential for abuse. Agonist medicines also offer the advantage of being inherently positively reinforcing (that is, activate the reward pathway), which usually improves medication adher-ence and increases engagement and retention in treatment.
Agonist pharmacotherapies are of particular interest in the treatment of ATS dependence because the most effective pharmacotherapies for opioid and nicotine dependence are agonist therapies. Methadone was introduced into Australia in 1970 in response to concerns about morbidity and mortality, and criminal activity associated with opioid use (McArthur, 1999). Through decades of rigorous investigation, methadone has demonstrated effectiveness in reducing heroin use and retaining people in drug treatment (Mattick et al., 2009), as well as reducing injecting behaviours and risk of mortality (Kimber et al., 2010). Users of ATS and heroin face similar risks and harms, such as needle sharing, exposure to blood-borne viruses, and engagement in criminal activity (McKetin & McLaren, 2005), suggesting agonist therapies are also a viable option as pharmacotherapy for ATS dependence.
The potential roles of agonist medicines in the treatment of ATS dependence include nor-malising neurochemistry; providing a stable, known and legal dose of a medicine that stimulates the central nervous system in ways that may be acceptable to users but lack the severe adverse effects of illict ATS; reducing illicit ATS use (quantity and frequency); and minimising physical withdrawal symptoms, including withdrawal-related craving that may trigger relapse (Brensilver, Heinzerling, Swanson & Shoptaw, 2012; Hartz, Frederick-Osborne & Galloway, 2001).
Due to their primary roles in ATS neurochemistry, the dopamine, serotonin and noradrena-line systems have been the targets for a range of agonist medicine treatment trials for ATS dependence. Dopamine depletion is a hallmark of ATS dependence and withdrawal. Two pharmacotherapies that are functional agonists are dexamphetamine and methylphenidate. They are both structually similar to methamphetamine and both have similar effects to meth-amphetamine on these important neurotransmitter systems. Both medicines act primarily on the dopaminergic pathways and on noradrenergic pathways, the latter often to a lesser degree.
Dexamphetamine is the dextrorotatory stereoisomer2 of the amphetamine molecule and a
psychostimulant drug that is approved for the treatment of attention deficit hyperactivity
disorder (ADHD) and narcolepsy. It has been trial ed as a replacement pharmacotherapy among
dependent ATS users in Australia and elsewhere. Dexamphetamine primarily increases release
of monoamines. Dexamphetamine is a functional agonist of methamphetamine, meaning
it produces similar pharmacological effects to methamphetamine, but has the advantages
of being able to be provided in a known and controlled dosage, similar to opioid–agonists
for opioid dependence. Dexamphetamine is structurally similar to endogenous monoamines
(noradrenaline, dopamine and serotonin), competing with them for uptake at monoamine
transporters, resulting in higher levels of monoamines at the synaptic cleft (Grabowski, Shearer,
Merrill & Negus, 2004). Higher doses of dexamphetamine also cause release of noradrenaline
and dopamine and, to a much lesser degree, serotonin (Howell & Kimmel, 2008).
Methylphenidate is a dopamine and noradrenaline re-uptake inhibitor approved for treat-
ment of attention deficit hyperactivity disorder; and has also been trialled as a replacement
pharmacotherapy among dependent ATS users. Methylphenidate primarily blocks re-uptake
of monoamines into the synapse, thereby increasing concentrations of monoamines at the
synaptic cleft.
Bupropion is an atypical, non-tricyclic antidepressant and smoking cessation aid thought to
act through noradrenaline–dopamine re-uptake inhibition. It also acts as a nicotinic acetyl-
choline receptor antagonist. It is considered for its role in reducing amphetamine withdrawal
symptoms that are associated with dopamine depletion. Bupropion has a mild stimulant
effect and antidepressant properties (Brensilver, Heinzerling et al., 2012), probably brought
about by restoring depleted levels of dopamine (Rau et al., 2005), and has been approved
for the treatment of depression, seasonal affective disorder, and smoking cessation.
Modafinil belongs to a relatively new class of wakefulness-promoting agents known as
eugeroics. In Australia it is approved for the treatment of narcolepsy, sleep disorder associ-
ated with shift work, and excessive daytime sleepiness associated with obstructive sleep
apnoea. The pharmacology of modafinil is complex and the exact mechanism of action is
not yet known (Ballon & Feifel, 2006), but recent research has found that modafinil appears
2 Isomers are molecules that have the same molecular formula as each other but differ in the way the atoms are arranged around the central atom, while dextrorotatory means the molecules rotate the plane of polarised light to the right (such rotation affects the pharmacological activity of molecules).
to act primarily on the dopamine transporter, inhibiting its re-uptake and leading to an increase in extracellular dopamine, though it does have non-dopaminergic mechanisms as well (Zolkowska et al., 2009).
Amineptine is an atypical tricyclic antidepressant that selectively inhibits the re-uptake of
s for amphetamine-type stimulant u dopamine, and to a lesser extent noradrenaline, and exerts a short-lived stimulant effect. This medicine is not currently available in Australia.
Preclinical studies have shown that blocking serotonergic transmission increases ampheta- mine consumption, which led researchers to investigate if an increase of serotonin at the synaptic cleft would reduce ATS use. In addition, a wide range of methamphetamine with-drawal symptoms appear similar to that of depression, providing a rationale for the use of serotonergic agonists for methamphetamine dependence treatment (Rose & Grant, 2008).
Fluoxetine is an antidepressant of the selective serotonin re-uptake inhibitor (SSRI) class.
SSRIs work by preventing uptake of serotonin into the neuron, thereby initially increasing
serotonin levels at the synaptic cleft, with longer-term effects being attributed to down-
regulation of presynaptic autoreceptors. Fluoxetine was found to reduce methamphetamine
self-administration in animal studies, sparking interest in its ability to reduce ATS use among humans.
Sertraline is an antidepressant of the selective serotonin re-uptake inhibitor class, approved
in Australia for the treatment of major depressive disorder, social anxiety disorders and
premenstrual dysphoric disorders. Early studies showed that inhibited serotonin signalling
caused animals to self-administer more ATS; therefore sertraline, which increases levels of
serotonin at the synaptic cleft, was considered a valid target of investigation among human
participants.
Mirtazapine is a noradrenergic and specific serotonergic antidepressant used primarily in
the treatment of major depressive disorders. It is thought to work by enhancing the release
of noradrenaline and serotonin (Anttila & Leinonen, 2001). Structurally, mirtazapine can
also be classified as a tetracyclic antidepressant. It has been trialled for the treatment of
ATS withdrawal symptoms because of the association of amphetamine withdrawal with
serotonin depletion.
Ondansetron is a serotonin receptor antagonist and modulator of cortico-mesolimbic dopamine
function. As many stimulants act through cortico-mesolimbic dopaminergic neurons, it is
hypothesised that a 5HT3 receptor antagonist may indirectly reduce cortico-mesolimbic
dopamine release (Johnson, 2007). It is approved in Australia for the management of nausea
and vomiting associated with radiotherapy being used to treat malignancy. It has been trialled
to determine its effectiveness in reducing the subjective rewarding effects of ATS among
dependent users and is currently being investigated for the treatment of alcohol use disorders.
GABAergic agents The gamma-aminobutyric acid (GABA) system has been found to play a key role in inhibit-ing synaptic transmission in the brain (Padgett & Slesinger, 2010). One possible mechanism to reduce the reinforcing effects of ATS and craving is through GABA agonists mediating transmission along the mesolimbic dopamine system, which is thought to reduce the reward-ing effects of ATS (Cousins, Roberts & de Wit, 2002). Therefore, a number of GABAergic medicines have been investigated for their potential role in treating ATS dependence.
Baclofen is a derivative of GABA and an agonist for GABA receptors. Baclofen is primarily
used to treat involuntary muscle spasm in multiple sclerosis and spinal lesions and is being investigated for the treatment of alcohol use disorders.
Gabapentin is a GABA agonist and anticonvulsant that increases GABA concentrations in
the central nervous system, possibly via inhibition of GABA-transaminase. Originally devel-
oped for the treatment of epilepsy, it can also be used under authority in Australia for the
treatment of refractory neuropathic pain not controlled by other drugs. Results from studies
showing gabapentin reduced craving for cocaine prompted interest in its role in treating
methamphetamine dependence.
Topiramate is an anticonvulsant (anti-epilepsy) drug that showed promise in the treat-
ment of alcohol and cocaine use, thus prompting investigations into its usefulness for ATS
users. While the proposed mechanism for how topiramate may work for methamphetamine treatment is not clear, topiramate is known to facilitate GABAergic transmission through a non-benzodiazepine site on the GABA receptor. Through its action on the GABAergic pathway, it is possible that topiramate may have an effect on the reward system by depressing dopaminergic transmission along the mesolimbic pathway (Elkashef et al., 2012). In Australia, topiramate is indicated only for the treatment of epilepsy in adults and children aged two years and over, and the prevention of migraine headaches in adults.
Vigabatrin (Gamma Vinyl GABA or GVG) is an analogue of GABA (but not a receptor agonist)
that has been shown to minimise the rapid rise of dopamine, and associated behaviours,
following ATS use. The ability of vigabatrin to reduce pharmacological effects of metham-
phetamine is thought to be how it may reduce methamphetamine use. In preclinical studies,
vigabatrin has been shown to block reinstatement of drug-related behaviors, suggesting
promise as a relapse prevention medication (DeMarco et al., 2009). It is prescribed in Australia
for the treatment of epilepsy that has not been successfully controlled by other medicines.
Flumazenil is a GABA antagonist available for injection only and used as an antidote in the
treatment of benzodiazepine overdose. It was thought to play a role in restoring balance,
impaired through chronic ATS exposure, in the GABA system.
Dopamine antagonists
Medicines that work as antagonists bind to the same receptors as the drug of concern and limit
its effects, but unlike agonists, these medicines exert no active effect (Brensilver, Heinzerling
et al., 2012). The usefulness of antagonist medicines is thought to be their ability to block
s for amphetamine-type stimulant u the rewarding, and therefore reinforcing, effects of the drug of concern, resulting in the eventual elimination of drug-using behaviours (Herin, Rush & Grabowski, 2010).
Evidence from studies of antagonist pharmacotherapies in the treatment of drug depend-encies other than ATS (such as naltrexone for alcohol and opioid dependence) has provided the basis for trialling dopamine antagonist pharmacotherapies, such as the antipsychotics class of medicines, with ATS users. However, the euphoric effects of ATS do not appear to be reduced by the dopamine antagonists risperidone or haloperidol (Rose & Grant, 2008), suggesting that these agents are not useful in the typical ‘antagonist' approach used with other substances such as opioids. As noted below, dopamine antagonists are commonly used to treat psychosis associated with amphetamine use.
Haloperidol is a dopamine antagonist of the typical (first-generation) antipsychotic class. It
is a butyrophenone derivative and has pharmacological effects similar to the phenothiazines.
Haloperidol is an older antipsychotic used in the treatment of schizophrenia and acute psychotic
states and delirium, and was trialled for its effectiveness to treat ATS-induced psychosis.
Atypical antipsychotics such as aripiprazole, olanzapine, quetiapine and risperidone differ from typical antipsychotics such as haloperidol due to the lesser degree of extrapyramidal (movement) side effects and constipation. The reduced side-effect profile is attributed to a more rapid dissociation from the dopamine receptor than the first-generation antipsychotic medicines, allowing more normal dopamine transmission and less effect of hormones, cogni-tion and extrapyramidal side effects.
Aripiprazole is a partial dopamine agonist and atypical antipsychotic with additional anti-
depressant properties used in the treatment of schizophrenia, bipolar disorder and clinical
depression; it has been trialled as a treatment for ATS-induced psychosis.
Olanzapine is an atypical antipsychotic. Olanzapine is a serotonin–dopamine antagonist
approved in Australia for the treatment of schizophrenia and related psychoses. Olanzapine
is structurally similar to clozapine, but is classified as a thienobenzodiazepine and has been
trialled for use in ATS-induced psychosis.
Quetiapine is an atypical antipsychotic and serotonin and dopamine antagonist, approved
in Australia for the treatment of schizophrenia and bipolar 1 disorder. Trialled for its effec-
tiveness in treating mood disorders and ATS dependence.
Risperidone is a dopamine antagonist of the atypical antipsychotic class of medicines,
approved in Australia as a treatment for schizophrenia and as adjunctive therapy to mood
stabilisers for treating acute mania associated with bipolar 1 disorder. Trialled as a treatment
for ATS-induced psychosis.
Opioid antagonists block the effect of endogenous (naturally occurring) opioids by binding to opioid receptors in the brain. It is hypothesised that, by blocking endogenous opioids, a change can be effected on the reinforcing properties of methamphetamine.
Naltrexone is an opioid receptor antagonist that exerts effects by blocking the effects of
heroin and other opioids. It is authorised for use in Australia in the management of opioid
dependence and alcohol dependence. Naltrexone has been shown to reduce cravings for alco-
hol and limit its rewarding effects when consumed. Opioid receptors are located on dopamine
cell bodies, partially modulating dopaminergic effects (Llorens Cortes, Pollard & Schwartz,
1979). Stimulant administration has also been shown to change opioid receptor density in
the nucleus accumbens, a brain region known to be associated with reinforcement of drug
administration (Azaryan, Coughlin, Buzas, Clock & Cox, 1996). As such, naltrexone has also
been examined for its role in tempering the rewarding effects of ATS among dependent users.
Pharmacotherapies to reduce craving
Dopamine pathways in the midbrain are thought to mediate the rewarding effects of meth-
amphetamine and be involved in cravings to use. A number of medicines have been trialled
to determine their effectiveness to reduce cravings among ATS users.
Amlodipine is a long-acting calcium ion antagonist used as an antihypertensive and in
the treatment of angina pectoris. By blocking calcium ion influx selectively on vascular
smooth muscle, amlodipine causes vasodilation, reducing vascular tone and blood pressure.
Amlodipine is thought to play a role in reducing the rewarding effects of ATS use by blocking
central dopamine pathways in the brain. Calcium-channel blockers have been proposed as
a treatment for methamphetamine dependence because of their observed ability to reduce
subjective effects of methamphetamine, by antagonising the effect of dopamine in central
dopaminergic pathways (Johnson et al., 2008).
Varenicline is a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, which
stimulates nicotine receptors more weakly than nicotine. As a partial agonist, it both reduces
cravings for, and decreases the pleasurable effects of, cigarettes and other tobacco products,
making it a candidate for trials among ATS users. In Australia, it is prescribed as an anti-
smoking aid.
Other medicines
Citicoline is a naturally occurring compound shown to reduce some of the functional impair-
ments associated with acute stroke and is thought to have neuroprotective properties and
to increase norepinephrine, dopamine, serotonin and acetylcholine levels in certain brain
s for amphetamine-type stimulant u regions. Used as adjunctive therapy for Parkinson's disease, it also showed promise in reducing craving for cocaine, and was therefore trialled among dependent ATS users.
N-acetyl cysteine, commonly known as NAC, is the precursor to both the amino acid L-cysteine and glutathione, and is thought to have a role in reversing glutamate dysfunction associated with drug cravings. It is sold over the counter in Australia as a dietary supplement, com- monly claiming antioxidant and liver-protecting effects. It is also used as a cough medicine.
Purpose of this review
Despite research efforts so far, no medications have widespread approval in Australia or internationally for the treatment of ATS dependence or withdrawal, leaving an important gap in evidence-based treatment options for clients and the health professionals who work with them. There is a broad range of views about the use of pharmacotherapy within the alcohol and other drug treatment sector generally, and specifically for the treatment of ATS dependence.
In the context of the lack of approval for routine use of medicines with ATS users and the breadth of opinion on the role and function of pharmacotherapy for this group, the purpose of this review of the evidence for pharmacotherapies for ATS treatment was to articulate the potential role for medicines in the treatment of ATS dependence and related condi-tions, including which medicines show potential, under what circumstances, and with which patients. The review is designed to help to guide the next steps, including the development and updating of clinical guidelines and identification of areas for concentration of future research efforts in Australia.
The reference group that guided the conduct of this review developed a number of research questions: 1. What medication treatment options are currently available, within Australia as well as internationally, for the treatment of dependent ATS users? 2. What are the areas of promising research for the treatment of dependent ATS users and the role Australian research might play? 3. What are the medication treatment options and what is their relationship to other treat- ment interventions? 4. What are the advantages and disadvantages of each of the medication treatment options? Methods
This review was undertaken using a systematic review method coupled with a modified
meta-narrative approach to the interpretation of findings. Systematic reviews use a thorough
systematic search method as the primary vehicle to include all relevant results in a summary
of the literature in an effort to answer a specific research question. A systematic review can
include any type of study (including qualitative and case studies), and differs from a general
review in that the search method and the evaluation of the articles are explicit and replicable.
Furthermore, it allows a systematic sorting of the evidence to answer specific questions.
A traditional systematic review works best when there are large numbers of studies with
similar methodologies and outcome measures.
A newer form of review has emerged to help researchers interpret the literature when methods, measures and outcomes vary widely. A meta-narrative review (Potts, 2012) or realist review (Pawson, Greenhalgh, Harvey & Walshe, 2005) is a pragmatic method of understanding a diverse and disparate literature. Meta-narrative reviews are typically used for distilling complex interventions (that is, areas in which there may be multiple components, multiple target groups or natural variability in the application of the intervention, such as evaluation of psychological treatments or policy interventions). Although the efficacy and effectiveness of medicines are generally considered a ‘simple intervention' (Wong, Greenhalgh & Pawson, 2009), the complexity of methamphetamine use has resulted in the reporting of widely varied research outcomes.
Rather than presenting and interpreting the evidence as ‘all-or-nothing' (that is, either the weight of the evidence is for or against the use of a medicine), a realist or meta-narrative review is designed to examine similarities and differences in the data and to look beyond ‘what' to ‘why', ‘how', ‘for whom' and ‘in what circumstances' (Wong et al., 2009).
Search strategy
Search terms were developed based on the aims and scope of the review. A combination of
MeSH (and other database thesaurus) terms, keyword terms and words in the text and title
were used. Groups of key terms were used for searches, then systematically combined for
exploring the various sets of clinical questions across all databases. The databases searched
were: MEDLINE, PsycINFO, Embase and the Cochrane Database of Systematic Reviews. The
search period was January 1997 to January 2013. Hand-searching of specific papers also
identified some additional studies.
Inclusion and exclusion criteria
The inclusion criteria were:
• human studies s for amphetamine-type stimulant u • adult studies • articles published between 1997 and 2012 (last 15 years) • manuscripts in English or with available English translation • Level IV or above intervention studies (National Health and Medical Research Council levels of evidence).
The exclusion criteria were: • animal studies • non-English manuscripts • studies published prior to 1997 • qualitative studies and general reviews • studies that included primarily non-dependent participants • studies that included primarily non-treatment appropriate participants or contexts (e.g. used healthy volunteers or used dependent volunteers in a laboratory setting) • studies of pharmacotherapy responses to acute toxicity.
Screening and extraction
At the first screen, one reviewer excluded all studies that were not related to ATS. At the
second screen, al studies that did not meet inclusion criteria were excluded (e.g. laboratory and
animal studies, participants without ATS dependence). Data from each article were extracted
by a single reviewer and checked and entered into a summary table by a second reviewer.
Analysis
Qualitative analysis, synthesis and interpretation of the data were undertaken by two review-
ers. Elements from the meta-narrative approach were used in the interpretation of the review
data. Details of the search, screening and review procedure are shown in Figure 1.
Number of citations retrieved through database searching (including duplicates): 6537
Number of citations identified through other sources: 52
First screen
Number of citations (duplicates & irrelevant records Number of studies excluded at second screen: 2021
Number of studies assessed for quality: 158
Final review
Number of studies included in final review: 56
Figure 1: Search, screening and review procedure
Detailed findings
Amphetamine and methamphetamine
Withdrawal from amphetamines
See summary evidence table beginning on page 48 for details of this group of studies.
s for amphetamine-type stimulant u Overall summary The results are not conclusive but, despite small sample sizes, some positive results were reported. Where medicines showed non-significant effects compared to placebo, both active treatment and placebo groups improved.
No evidence was found for the use of benzodiazepines or other medicines for the manage-ment of sleep disturbance or agitation among ATS users in withdrawal, even though these medicines are commonly recommended in clinical guidelines.
Of the four medicines examined, modafinil, mirtazapine and dexamphetamine appear to have some effect during withdrawal and may also assist with relapse prevention. Although 300 mg of amineptine (the fourth medicine) appears to be effective, there is some ques-tion about its abuse potential and it is currently unavailable in Australia.
The evidence from this review, although limited, suggests that modafinil, mirtazapine and dexamphetamine may have a potential role in the range of symptom-management strategies available for methamphetamine withdrawal and merit further investigation. There is some evidence for the use of these medicines, which is more evidence than currently exists to support other commonly recommended pharmacotherapy for ATS withdrawal, such as benzodiazepines, which are used to reduce agitation.
In summary, the research shows that: • 60 mg of mirtazapine demonstrated effectiveness in reducing withdrawal symptoms in some participants over a 14-day period; lower doses did not produce convincing effects • 400 mg of modafinil demonstrated effectiveness, when tolerated by patients, in reduc- ing withdrawal symptoms in some participants over a 7–10 day period; lower doses did not produce convincing effects • 60–110 mg of dexamphetamine demonstrated effectiveness in reducing withdrawal symptoms in some participants over a period of 2–8 weeks.
No serious adverse events were reported in these studies, suggesting that among both moderately and heavily dependent individuals these medicines appear to be safe for use in ATS treatment. However, there were a small number of studies, most with small sample sizes, and a lack of strong evidence either in favour of or against the efficacy of these medicines. Although mirtazapine, modafinil and dexamphetamine show promise, further research is needed to confirm the effectiveness of these medicines for withdrawal. Given ATS treatment has a high drop-out rate and a high relapse rate during withdrawal, this may be a worthy area for future research to assist in retaining users in a supervised withdrawal program.
Future clinical guidelines should detail the circumstances under which these medicines could be used, and for whom, and the medical monitoring strategies that would ensure their safe use.
Summary of literature reviewed Two systematic reviews have been conducted by researchers from the Cochrane Collaboration (Shoptaw, Kao, Heinzerling & Ling, 2009; Srisurapanont, Jarusuraisin & Kittirattanapaiboon, 2001). Both found favourable results overall for two studies involving amineptine; and Shoptaw and col eagues found mixed results for mirtazapine. Since then, another five relevant papers have been published. In total, seven papers from six separate studies of medicines for withdrawal, and two studies of maintenance medicines, which also measured withdrawal symptoms, were included in this review.
Of the nine included studies, two examined mirtazapine (Cruickshank et al., 2008; Kong-sakon, Papadopoulos & Saguansiritham, 2005), one studied modafinil (Hester, Lee, Pennay, Nielsen & Ferris, 2010 from the same study; Lee et al., 2013), one trial involved modafinil and mirtazapine (McGregor, Srisurapanont, Mitchell, Wickes & White, 2008), three studied amineptine (Jittiwutikan, Srisurapanont & Jarusuraisin, 1997; Srisurapanont, Jarusuraisin & Jittiwutikan, 1999; Srisurapanont et al., 2001) and two dexamphetamine maintenance trials that reported withdrawal symptom outcomes (Galloway et al., 2011; Longo et al., 2010) were also reviewed.
The results of these studies were mixed, with one modafinil study (Lee et al., 2013) and two mirtazapine studies (Cruickshank et al., 2008; McGregor et al., 2008) finding no differences in withdrawal or other measures compared to placebo, with others finding significant dif-ferences in favour of mirtazapine (Kongsakon et al., 2005) and modafinil (McGregor et al., 2008). Both dexamphetamine studies showed a significant reduction in severity of withdrawal symptoms (but not drug use). All of the studies had very small sample sizes.
All four medicines were well tolerated at a wide range of doses given with no serious adverse effects reported and some indication of positive clinical effects from some studies, suggesting that these medicines remain a possibility for assisting with symptom management during withdrawal and merit further investigation.
Modafinil also resulted in neuropsychological improvements and dexamphetamine resulted in reduced craving, both of which could have implications for relapse prevention, although the longer-term benefits of maintenance medication prescribed during withdrawal have not been examined in any studies.
In each of the reviewed studies, those taking the active medicines improved on measures of withdrawal symptoms and there were no serious adverse effects reported, suggesting that these medicines are generally safe to use during withdrawal under supervised conditions. s for amphetamine-type stimulant u As with most medicines, there were mild side effects such as nausea and headache in a minority of patients.
All of the studies had relatively small sample sizes: the smallest had 19 participants and the largest had 60 participants. At these sample sizes it would be difficult to detect small differ-ences that may be clinically significant in a withdrawal situation. A meta-analysis may help to clarify whether differences exist but there were only one or two studies of each medicine, and while meta-analysis is possible with small numbers of studies, it is less reliable.
There was no evidence found for the use of benzodiazepines or other medicines for the management of sleep disturbance, agitation or other psychiatric symptoms among ATS users in withdrawal, although benzodiazepines are commonly recommended in clinical guidelines (e.g. Dunlop, Hocking, Lee & Muhleisen, 2004; Dunlop et al., 2008; Kenny et al., 2009; Lintzeris, Dunlop & Thornton, 1996) for use under supervision. Future revisions of these guidelines should carefully consider recommendations for the use of medicines that are based on evidence for other illicit drug withdrawal.
Of the three papers that reported withdrawal outcomes after treatment with modafinil, McGregor et al. (2008) reported significant effects on withdrawal symptoms, and Hester et al. (2010) reported significant effects on cognitive functioning, specifically on immedi-ate memory and executive functioning. Lee et al. (2013) found no benefit on withdrawal symptoms or on retention in withdrawal treatment. Of the participants who left withdrawal treatment early, most of those who had been in the placebo group, but not those who had been in the modafinil group, resumed ATS use, suggesting some benefit. However, the sample size for this study was small.
McGregor et al. (2008) found significant differences in withdrawal symptoms using modafinil. This study used higher doses of modafinil (400 mg) than Lee et al. (2013) (200 mg), possibly explaining the differences in response. In addition, the former was an open-label study. Placebo medicines have been shown to positively influence patients' self-reported symptoms (Hróbjartsson & Gøtzsche, 2010) and there may have been a placebo effect in the McGregor study. The larger dose of 400 mg did not produce significant side effects but appeared to result in a better outcome.
Two mirtazapine studies showed positive benefits and one did not. Kongsakon et al. (2005) reported significant effects of mirtazapine at 15–30 mg. McGregor et al. (2008) reported large and significant benefits of mirtazapine over treatment as usual (but not modafinil) at 60 mg. Cruickshank et al. (2008) reported small and non-significant effects at 30 mg. Larger doses appeared to produce larger effects with no significant adverse events reported. McGregor et al. (2008) conducted an open-label study and there may have been some placebo effect.
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-ment entry. Galloway et al. (2011) used a dose of 60 mg and found significant effects of dexamphetamine in reducing withdrawal symptoms and craving among mainly moderate methamphetamine smokers (17 days in the previous month), and Longo et al. (2010), using a dose of 20–110 mg, found a non-significant trend (with a small sample size) in reduction of withdrawal symptoms among mainly long-term (11 years) injecting methamphetamine users. Although limited, these results suggest that dexamphetamine is promising for the treatment of ATS withdrawal in moderate users, but further research is required. A meta-analysis may be possible.
Since amineptine is not currently available as a medicine, no further distilling of the results was undertaken.
There are numerous guidelines that recommend a range of medicines for the management of withdrawal symptoms in ATS users (e.g. Dunlop et al., 2004; Dunlop et al., 2008; Kenny et al., 2009; Lintzeris et al., 1996). These guidelines are based on recommendations for the management of other drug withdrawal, which reflects the paucity of research into the pharmaceutical management of ATS withdrawal.
Relatively few studies of pharmacotherapy for amphetamine withdrawal were found, high-lighting a sizeable research gap. Given the poor treatment completion rates (50%) and high rates of relapse immediately after withdrawal (50%), it appears to be an area that would benefit from more intensive research efforts (Brecht et al., 2005; McKetin et al., 2005).
The variability in results and small sample sizes suggest that the studies suffered from low power, and larger studies are needed to show more conclusive results. Many studies did not report important factors, such as average doses (where a variable dose schedule was used) and outcome means, in enough detail to assist in clinical decision making. This suggests the need for more detailed and standardised approaches to the reporting of pharmacotherapy trials is required. As a start, a meta-analysis pooling the results of multiple studies may assist in clarifying outcomes. This was beyond the scope of the current work.
Treatment for amphetamine dependence
See summary table beginning on page 58 for details of this group of studies.
Overall summary s for amphetamine-type stimulant u Thirty-nine studies were identified, examining 18 potential pharmacotherapies. None demonstrated consistent evidence of effectiveness in reducing ATS use or preventing relapse among dependent methamphetamine users.
Although there have been many pharmacotherapies examined, each medicine has been the subject of relatively few studies. Dexamphetamine has been the subject of the greatest number (seven, including four RCTs), followed by modafinil (five, including three RCTs) and bupropion (four, all RCTs). The evidence is sparse for the remainder. In addition, the studies conducted to date are all smaller-scale feasibility studies. This is consistent with a treatment area in its relative infancy, but now larger RCTs are required.
The following medicines appear to be well tolerated and showed some significant positive effects in the literature reviewed: • Dexamphetamine reduced the severity of dependence in some participants and increased treatment retention. The most effective dose reported in the literature appears to be 100 mg per day taken in the morning to limit sleep disturbance.
• Modafinil was found to be superior to placebo in reducing ATS use among those who were medicine-compliant. The most effective dose was 400 mg per day taken in the morning to limit sleep disturbance.
• Bupropion was effective in reducing ATS use by ‘lighter' ATS users (<18 days use per month). The most effective dose reported was a starting dose of 150 mg per day increasing to 300 mg per day after three days taken either in the morning or in divided doses (150 mg morning and 150 mg evening). Bupropion may be especially useful for men and for those with a lighter pattern of ATS use.
• Naltrexone may improve retention in treatment and reduce craving to use ATS. The most effective dose was 50 mg per day (optimal time for daily dosing was unspecified).
• Methylphenidate may improve retention in treatment and reduce use. The most effective dose seems to be a starting dose of 18 mg increasing to 36 mg in the second week and 54 mg from week 3 (optimal time for daily dosing was unspecified).
Without further research, these medicines cannot yet be considered as routine treatment options for dependent methamphetamine users, but do appear to offer some benefit to some people, and there were few adverse events reported. Most of the studies were con-ducted over 8–12 weeks, so the effective and safe long-term use of these medicines is unknown. As these medicines showed some benefits, future research efforts could focus on treatment matching and identifying particular subgroups of ATS users that may benefit most from these medicines.
There were a number of other medicines that showed promise and, hence, may also be good candidates for further research: • varenicline.
Other medicines showed either no benefit or an unacceptable adverse effect profile and do not appear to be of value clinically or for future research: • baclofen (limited evidence of benefit) • gabapentin (limited evidence of benefit) • ondansetron (limited evidence of benefit) • amlodipine (limited evidence of benefit) • aripiprazole (evidence of adverse effects) • vigabatrin (evidence of adverse effects) • sertraline (evidence of adverse effects) • Prometa™ protocol of combination flumazenil and gabapentin (evidence of adverse Overall, the studies showed variable outcomes and some results were conflicting, even under robust study conditions. Many had small sample sizes, while poor study retention and failure of many participants to take medicines as prescribed were common barriers to gaining high-quality results. Australians tend to use ATS in patterns that differ from users in other countries (e.g. higher rates of injecting), and as most of the evidence has been gained from international studies, further research is needed to examine the effectiveness of medicines that show promise for treating ATS-dependent adults under local conditions.
Summary of literature reviewed Thirty-nine studies were identified, examining 18 potential pharmacotherapies. Thirty-five of these studies reported no serious adverse events. All medicines come with some side effects and risks, and on occasion particular individuals may have unusual responses to some s for amphetamine-type stimulant u medicines, but overall there was no evidence that, at the doses reported, these medicines produced significant adverse effects, even in patients severely dependent on ATS.
None of these medicines showed effects across the main variables of reduced ATS use or abstinence that were strong enough to recommend their routine use, probably due to small sample sizes. But a number did show some promise, which may make their use in particular circumstances with specific patients under well-monitored conditions feasible. Meta-analysis may be useful in further assessing the viability of these medicines. Future clinical guidelines should detail the circumstances under which these medicines could be used, and for whom, and the medical monitoring strategies that would ensure their safe use.
Although a wide variety of medicines have been trialled, most individual medicines have been the subject of only a few studies, with only three medicines having more than three published reports (dexamphetamine (n=7), modafinil (n=5) and bupropion (n=4)), and not all of those studies were RCTs. Thus, although studies have been accruing over a long period of time and with a large number of medicines, the research into pharmacotherapies for amphetamine dependence is in its relative infancy. Many of the studies are typical of early studies of any pharmacotherapy; that is, they are case studies, open-label studies or feasibility RCTs. None has been a study with a very large sample size. For example, the largest sample among the four dexamphetamine randomised controlled trials numbered 60 participants.
Medicines showing some benefit in randomised controlled trials
Five medicines (dexamphetamine, methylphenidate, modafinil, bupropion and naltrexone) showed equivocal but promising results, suggesting they may be effective targets for further research. Each of these medicines has been the subject of more than one peer-reviewed report and has shown some benefits over placebo on some variables or within some groups of participants. None reported any serious adverse events.
Dexamphetamine showed benefit over placebo on secondary variables of retention in treat-
ment and attendance at counselling sessions, and may reduce the severity of dependence
(Longo et al., 2010; Shearer et al., 2001).
Methylphenidate was superior to placebo in reducing amphetamine use in one study ( Ti honen
et al., 2007) but not in a second study (Miles et al., 2013).
Modafinil: Two RCT studies showed that those who were compliant with taking the medicine
were significantly more likely to reduce drug use (Anderson et al., 2012; Shearer et al., 2009).
Bupropion appears to be associated with reduced methamphetamine use among men but
not women (Elkashef et al., 2008), and among those with ‘lighter' patterns of use (<18 days
in a month) (Elkashef et al., 2008; Shoptaw et al., 2008). In a re-analysis of two randomised
controlled trials of bupropion, Brensilver, Heinzerling et al. (2012) found that the inability
to produce at least three drug-free urine samples in the first week of treatment was associ-
ated with a 90 per cent likelihood of treatment failure. They concluded that, in a clinical
setting, failure to achieve at least two drug-free urine samples in the first three weekly visits
represents a high risk for treatment failure. When abstinence is the goal, urine testing may
help to indicate the likelihood of treatment success.
Naltrexone: One RCT study (Jayaram-Lindström, Hammarberg, Beck & Franck, 2008) found
lower amphetamine use, reduced craving and better retention among the naltrexone group
compared to placebo but a second smaller RCT study found no differences.
These findings are consistent with, and were built upon by, a review by Brensilver et al. (Brensilver, Johnson, Grotheer, Heinzerling, Bholat & Shoptaw, 2012), which concluded that bupropion, methylphenidate and naltrexone are among the most promising medicines to date.
Medicines that may have potential but require further research
A number of medicines show promise but the number of studies is too small to draw conclu- sions. Many of them have shown some benefits, but have done so in either a single small n RCT study or one or more non-RCT studies.
Mirtazapine has been the subject of only one study, an RCT, which showed significant
decreases in methamphetamine use and sexual risk taking (Colfax et al., 2011). Brensilver,
Johnson et al. (2012) also highlighted the potential benefits of mirtazapine. But fewer than
50 per cent of participants took the medicine regularly as prescribed, suggesting it may be
more useful for those who are highly motivated to reduce their use.
Fluoxetine: A single double-blind RCT (Batki et al., 1999) found fluoxetine was not superior
to placebo in reducing both self-reported and urinalysis-confirmed methamphetamine use,
but craving was lower in the fluoxetine group compared to the placebo group.
Topiramate: One large double-blind multi-site RCT (Elkashef et al., 2012) showed topiramate
was ineffective among study completers in promoting methamphetamine abstinence but
was superior to placebo on reducing use and severity of dependence and increasing general
functioning.
Risperidone: Two open-label uncontrolled trials by the same research group (Meredith,
Jaffe, Yanasak, Cherrier & Saxon, 2007; Meredith et al., 2009) found in favour of oral and
injectable risperidone on measures of methamphetamine use, craving, verbal memory and
psychiatric symptoms.
Varenicline: One recent pilot RCT (Swanson, Shoptaw & Heinzerling, 2011) reported greater
retention rates and trends in favour of varenicline over placebo in reducing methamphetamine use and increasing duration of abstinence compared with placebo.
Medicines with limited or no evidence of benefit
Gabapentin: One double-blind RCT (Heinzerling et al., 2006) found no effect for gabapentin
in reducing methamphetamine use, craving or retention when compared to both baclofen
and placebo.
s for amphetamine-type stimulant u Baclofen: One RCT (Heinzerling et al., 2006) found the GABA agonist baclofen was not
superior to placebo overal on measures of methamphetamine use, craving or treatment reten-tion. However, participants with greater medicine adherence showed a significant reduction in methamphetamine use when compared with placebo, but the short half-life of baclofen compared to the long half-life of ATS may limit its use.
Ondansetron: One RCT (Johnson et al., 2008) reported that ondansetron was well tolerated
by participants but was not superior to placebo on measures of methamphetamine use,
craving or severity of dependence. The treatment groups showed poorer outcomes (non-
significant) than the placebo group.
Amlodipine: One RCT (Batki et al., 2001) found no effect for amlodipine on any measures.
This report was a conference abstract with little detail about the direction of any changes.
Medicines with unacceptable side-effect profiles
The results suggest some medicines should not be used due to unacceptable side effects, including aripiprazole and vigabatrin (both of which appear to have potentially serious adverse effects) and sertraline and the Prometa™ protocol of combination flumazenil and gabapentin (both of which appear to increase amphetamine use).
Aripiprazole: The subject of one trial that had to be discontinued because of serious adverse
events. Participants in the aripiprazole group produced significantly more positive ATS urine
samples and showed a worsening of symptoms.
Vigabatrin: A single open-label study of vigabatrin did not show any unusual visual field
defects, but given that defects have been reported previously (including permanent vision
impairment), and this study was a small open-label trial with few benefits, future research
efforts should focus on medicines with greater promise.
Sertraline: There were two reports of the outcomes of sertraline (different analyses of the
same data set). They showed increases in use during the trial period and one of these analyses
also showed poorer retention and more adverse events than placebo (Shoptaw et al., 2006;
Zorick, Sugar, Hellemann, Shoptaw & London, 2011).
Combination flumazenil and gabapentin: In one study of combination flumazenil and
gabapentin, ATS use steadily increased during the trial from day 1 to day 30 in both placebo
and treatment groups, although the results show a large decrease in ATS use from 30 days
pre-trial to week 1 of the trial (Urschel, Hanselka & Baron, 2011). The initial decrease may
have been a response to entering treatment, as the placebo group also showed a similar level
of reduction. In addition, the protocol is complex to administer.
Numerous studies have been undertaken to identify a pharmacotherapy for methampheta-mine dependence. All have examined reduction in drug use or abstinence as the treatment goal across a spectrum of users. Further work should focus on areas of potential benefit and could include: • meta-analytic review of modafinil, dexamphetamine and bupropion studies; the data currently reported in these studies were insufficient for meta-analysis, but access to the original data sets or further details of these analyses would enable such an analysis • re-analysis of some of the larger data sets or designing studies that identify subgroups of ATS users which may show a differential benefit from these medicines as distinct from the sample as a whole • studies that examine the relapse–prevention potential of these drugs in abstinent users (for example, a random discontinuation design in which all patients undergo supervised withdrawal from ATS and are treated with the target medicine, then one group is with-drawn from the medicine according to random allocation) • further trials of methylphenidate, as it showed positive outcomes in one study and rep- lication is required • further trials of mirtazapine, baclofen and topiramate, which showed promise but have been the subject of only one study each.
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 adherence may be useful. Contingency management shows promise in supporting adherence to the pharmaceutical protocol. At least one study noted the requirement for daily dosing may have reduced adherence (Miles et al., 2013), so more flexible dosing regimes could be considered for future clinical trials.
Other considerations in the treatment of amphetamine dependence Role of adherence with prescribed medicines
In most of these studies, adherence to taking medicines as prescribed was low. Many stud-ies found a correlation between adherence and better outcomes, suggesting that if any of these medicines are used, monitoring of adherence is important for ensuring effectiveness of treatment. In some studies attrition rates were very high, also suggesting that assistance with maintaining motivation is an important factor in optimising client outcomes in a clinical setting.
Role of psychosocial interventions
Nearly al the studies utilised psychosocial interventions, some quite intensively, in conjunction with pharmacotherapy. Although attendance at treatment sessions varied between studies, psychosocial interventions for both the treatment and placebo groups may have masked the s for amphetamine-type stimulant u apparent effectiveness of the medicines being examined, making it difficult to determine the effect of the medicine itself. Psychosocial interventions, such as the Matrix Model (Rawson et al., 1995) used extensively in the United States and the Australian gold standard four-session brief cognitive behavioural and motivational interviewing (MI) intervention (Baker et al., 2005), have been shown to be effective for methamphetamine users. The Matrix Model is an intensive intervention involving group and individual work designed for dependent users in treatment. Baker and colleagues' combined MI/CBT intervention has been shown to be effective for a range of users, including those who are dependent.
A further complicating factor is that many of the studies employed intensive assessment procedures as part of the protocol. There is evidence to suggest that assessment itself is therapeutically beneficial (Kypri et al., 2007) and in some studies may have created a ceiling effect in the results that is unlikely to be replicated in the clinical setting.
The majority of the studies have been undertaken in the United States. This is significant for Australia because the nature of methamphetamine use and the treatment systems are different in the two countries. Among Australians who use drugs by injection, around 70 per cent used ATS (Stafford & Burns, 2012), and studies from the United States rarely included injecting methamphetamine users. Care is needed in translating results from international studies to the Australian clinical setting.
Subgroups of amphetamine users
Very little evidence is available concerning which medicines prescribed under what conditions might benefit particular subgroups of ATS users. Clinical experience suggests that people who use lower quantities of ATS at initial presentation may do better in treatment than those who are heavy users. This view was supported by results from two separate studies. Elkashef et al. (2008) showed that, for the subgroup of participants who had lighter use of methamphetamine at baseline, bupropion treatment increased weekly periods of abstinence (56%) compared to placebo (40%), and lighter users also showed a greater rate of decrease in urine quantitative methamphetamine than placebo. Shoptaw et al. (2008) also found that lighter users were nearly three times more likely to have a methamphetamine-free week than heavier users during treatment with bupropion compared with placebo. Although bupropion did not show benefit overall, post-hoc analyses suggest that there may be some benefit for lighter users (e.g. <18 days of use in the last 30 days).
Gender differences in outcomes were rarely reported in the studies reviewed. However, Elkashef et al. (2008) showed that bupropion was associated with reduced methamphetamine use in males but not in females.
Comorbid disorders may also complicate clinical responses to medicines. Shearer et al. (2009) found poorer outcomes for HIV-positive participants taking modafinil and poorer outcomes for methamphetamine-dependent participants with comorbid opioid dependence compared to those dependent solely on methamphetamine.
Vaccines for amphetamine dependence
There were no Phase II or III studies of vaccines identified, but they have been mooted for ATS users after successful trials with cocaine users.
Effective vaccines for many common illnesses, such as measles and polio, have been avail-able for many years. Vaccines are designed to boost the body's immune response against 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 passive vaccines introduce pre-generated antibodies.
Promising results from trials of vaccines for cocaine dependence (e.g. Martell et al., 2009) prompted a search for a vaccine for methamphetamine dependence. Methamphetamine vaccines are designed to sequester the methamphetamine molecules in the bloodstream and allow natural clearance to occur (Gentry, Ruedi-Bettschen & Owens, 2009). Without anti-bodies crossing the blood brain barrier, the highly rewarding central nervous system effects of methamphetamine would also be blocked.
To date, al trials of methamphetamine vaccines have been conducted in animal models. Early trials of active methamphetamine vaccines in rats found that while anti-methamphetamine antibody titres increased, behavioural effects of methamphetamine (e.g. locomotor activity) did not reduce (Gentry et al., 2009), indicating that methamphetamine was still active in the central nervous system, which is undesirable following vaccination. In later trials, six methamphetamine immunoconjugates were tested in mice with some found to result in high methamphetamine-antibody titres and high affinity (binding of molecules in the bloodstream) (Moreno, Mayorov & Janda, 2011). One of these promising immunoconjugates, MH6, was recently re-tested and found to again produce high methamphetamine-antibody titres and methamphetamine blood concentrations, and lower brain methamphetamine concentrations in rats (Miller et al., 2012), which adds to the promising pool of results in these pre-clinical trials of methamphetamine vaccines.
Researchers suggest that a successful vaccine could be a highly effective adjunct to prevent-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 medical settings (Gentry et al., 2009).
Table 1. Overview of studies reviewed for the treatment of amphetamine-type stimulant dependence
gabapentin
s for amphetamine-type stimulant u placebo; but equivocal use or have evidence use or have medication May reduce Increased dependence retention rates of mild and well a very high studies only; had to be studies had abandoned a high drop- for safety of benefit rating Shows some Shows Complicated Shows evidence of limited, but indications evidence of evidence of indications of reducing and may of reducing potential dependence, use and potential in medication- but evidence is limited Evidence of benefit rating legend: ★★★ Shows some benefit ★★ Shows potential benefit but current evidence is limited ★ Shows little or no evidence of benefit × Shows evidence of harm Treatment for co-occurring mental health problems among
amphetamine-type stimulant users
See summary table beginning on page 102 for details of this group of studies.
s for amphetamine-type stimulant u Overall summary It is difficult to draw any firm conclusions about the prescription of medicines for mental health disorders co-occurring with amphetamine use because of the nature of the studies.
A range of medicines, including antipsychotics, dexamphetamine, modafinil and citicoline, are probably safe and may be effective for methamphetamine users if used within existing guidelines for general population prescribing under close supervision.
Dexamphetamine and modafinil did not appear to exacerbate psychotic symptoms in the participants taking part in these studies, although Shearer et al. (2009) advise caution when using modafinil in those with pre-existing psychotic conditions. Dexamphetamine, risperidone and a combination of modafinil, quetiapine and divalproex appeared to have some positive effects on both psychotic symptoms and amphetamine use.
Although there was a paucity of well-controlled studies, those available suggest that medicines for mental health disorders in the general population are also suitable for amphetamine users with these disorders, under close supervision. Medicines to treat mental health disorders in the general population are probably useful and safe for people using amphetamines but, given the lack of specific evidence, additional monitoring may be required.
The dominance of case studies with the lack of standard measures makes it difficult to draw specific conclusions about the effectiveness of these medicines for people who use amphetamines and further research is needed.
Summary of literature reviewed A total of eight studies, two controlled trials (Brown & Gabrielson, 2012; Nejtek et al., 2008) and six case studies or open-label trials (Camacho, Ng & Frye, 2010; Camacho & Stein, 2002; Carnwath, Garvey & Holland, 2002; Misra & Kofoed, 1997; Misra, Kofoed, Oesterheld & Richards, 2000; Sulaiman et al., 2012) were reviewed.
There were very few studies that examined medication for co-occurring mental health problems among dependent amphetamine users, making it difficult to draw conclusions for clinical practice.
One study (Brown & Gabrielson, 2012) was a randomised trial that found improvement in depressive symptoms, but no change in drug use using citicoline, a naturally occurring compound thought to have neuroprotective properties, which is available as an over-the-counter supplement in the United States but not in Australia.
A second randomised trial (Nejtek et al., 2008) compared risperidone and quetiapine, two antipsychotic medicines, for amphetamine use and bipolar disorder and showed that both medicines improved manic and depressive symptoms and reduced cravings among this group. As no placebo control was employed, the most that can be said is that risperidone and quetiapine are equally effective, but it is unclear whether they are better than no treatment or other treatments. A number of other antipsychotic preparations have been examined for amphetamine users experiencing psychotic symptoms, including risperidone (Misra & Kofoed, 1997), olanzapine (Misra et al., 2000) and aripiprazole (Sulaiman et al., 2012), all of which were effective in reducing acute and residual psychotic symptoms in amphetamine users.
In a report of a single case, Camacho et al. (2010) concluded that a combination of modafinil, quetiapine and divalproex for methamphetamine users with bipolar affective disorder improved depressive symptoms and reduced craving for methamphetamine with no exacerbation of manic symptoms. The same group (Camacho & Stein, 2002) found that modafinil was also useful in treating a single case of social phobia and amphetamine dependence. It is important to note, however, that Shearer et al. (2009) suggest caution when prescribing modafinil for people with pre-existing anxiety or psychotic disorders, as the few reports of thought disorder or anxiety symptoms found in that study were unique to the modafinil group.
One case study (Carnwath et al., 2002) found that dexamphetamine, prescribed as replace-ment therapy for amphetamine dependence, did not exacerbate psychotic symptoms among a group of eight dependent amphetamine users with schizophrenia. Six of the eight patients showed ‘good' or ‘some' improvement in both drug use and mental health symptoms.
Overall, these studies do not offer sufficient evidence on which to base recommendations for the treatment of amphetamine use and co-occurring mental health problems. However, similar to general studies of co-occurring drug use and mental health disorders, they appear relatively safe for use with this group and may be helpful in treating symptoms of mental health problems among the cohort of amphetamine users of interest to this review.
There were few studies examining medicines for amphetamine use and co-occurring mental health disorders, and only two of the studies reviewed were controlled trials. All others were either open-label trials with no control group and small sample sizes, or single-case designs. Additional high-level studies of the efficacy and effectiveness of prescribed medicines for co-occurring mental health and ATS dependence are required.
Overall summary There were only two studies of treatment for MDMA, both single case studies of little s for amphetamine-type stimulant u value to clinical settings.
There is little evidence for the effectiveness of pharmacotherapy for MDMA and, with the exceptions of symptomatic relief from co-occurring mental health symptoms, psychosocial intervention remains the treatment of choice for this group.
Research efforts are better directed towards treatment of methamphetamine dependence because, although there have been reports of MDMA dependence and long-term prob-lems, these are unusual and rarely in isolation from polydrug dependence. MDMA use is generally considered to be self-limiting over time. Most issues with MDMA are acute and more amenable to harm reduction strategies.
Summary of literature reviewed Only two studies that examined the role of medicines for treating 3,4-methylenedioxymethyl-amphetamine (MDMA) use problems were identified and both were single-case designs. The first described the case of a 28-year-old man using MDMA two to four times per week for four years, who reported a dramatic reduction in MDMA use during three months of treat-ment with topiramate and a reduction in subjective effects of MDMA when it was taken (Akhondzadeh & Hampa, 2005). The second study reported the case of 28-year-old woman who reported depression and anxiety, which she linked to a period of one year when she used MDMA weekly; she had been abstinent for six years at the time of the study (Fetter, 2005). The patient self-reported decreased panic attacks and improved functioning use following three months treatment with mirtazapine.
Most of the problems associated with MDMA involve acute toxicity and it is rare for MDMA to be associated with chronic heavy use. There are a few reports of MDMA dependence in clinical settings and there is some evidence that a dependence syndrome potentially exists (Degenhardt & Hall, 2010), but presentation for treatment is relatively rare as a primary drug of concern. In 2011–12, for example, there were 720 closed treatment episodes across Australia for ecstasy as a main drug of concern, compared to 12 528 for amphetamines (Australian Institute of Health and Welfare, 2012). Given the small numbers of dependent users, research into pharmacotherapies is likely to offer more productive public health benefits if focused on treating amphetamine dependence.
Other amphetamine-type stimulants
Only one study that examined the role of medicines for treating stimulants other than
methamphetamine and MDMA was identified in this review and it was a single-case design.
The study described the case of a 37-year-old woman with a history of major depression,
eating disorder and compulsive behaviour who had used ephedrine for 20 years for weight
management. She was treated successfully with fluoxetine plus aripiprazole for eight weeks
and was ephedrine-abstinent after four months.
Very few ATS other than amphetamines become problematic among users. Given the small numbers of users, research efforts are likely to be better focused on treating methamphetamine dependence.
Conclusions
Amphetamine-type stimulants have been available on the illicit drug market in Australia
for decades and, like many drugs of abuse, their popularity has waxed and waned over the
years in accordance with availability, cost and cultural trends among people who use drugs.
ATS include amphetamines (amphetamine and methamphetamine), as well as MDMA and
a handful of other analogues not commonly seen among clients in treatment settings.
s for amphetamine-type stimulant u Methamphetamine has dominated the market since a significant spike in reported use in 1998 (Australian Institute of Health and Welfare, 2011), and recent data from the Drug Use Monitoring in Australia project (Sweeney & Payne, 2012) suggest that ATS use is once again on the increase since downturns were first reported in 2004.
The acute effects of ATS in general, and methamphetamine in particular, are highly rewarding for most people and users report feeling intense pleasure that is unrivalled by endogenous processes. Conversely, adverse effects can also be severe and include a range of significant physical and psychological health problems, including neurotoxicity. Despite this, people who use ATS tend not to present for treatment until their problems are extreme (Baker et al., 2004).
Research suggests that services generally have difficulty attracting ATS users into treatment and retaining them until treatment goals are met (Vincent et al., 1999). This could be due in part to the traditional focus of the alcohol and other drugs treatment sector on treating opiate and alcohol-use disorders, coupled with a previous paucity of evidence-based inter- ventions to offer people who use ATS.
There is now a significant body of evidence for the effectiveness of psychological therapies for problematic ATS use which can be used to guide clinical responses in all alcohol and drug treatment services (Lee & Rawson, 2008). Despite this, substantially fewer ATS users present for treatment than estimates suggest would benefit from it, and drop-out among people who do begin psychological therapy is high.
Practitioners have identified the lack of a pharmacotherapy for ATS as a barrier to treat-ment (Kenny et al., 2011), but to date the role that pharmacotherapy might play in better supporting people who are dependent on ATS is still unclear.
It is possible that offering dependent ATS users access to effective medicines may have several benefits. Firstly, it may serve to attract more people into treatment, and attract them earlier when evidence suggests they will benefit most. Secondly, offering pharmacotherapy in concert with psychosocial interventions may help to retain people in care until such time as treatment gains are made. This is particularly important for those people who have had multiple attempts at quitting or reducing ATS use on their own or under supervision, or for those who have been unsuccessful in maintaining engagement with psychosocial treatment services and have dropped out of treatment multiple times.
To date, there are insufficient data to demonstrate a universal benefit for any one particular medicine in the treatment of ATS use disorders over another, thus no medicines are authorised in Australia for this purpose and none can be recommended as a first-line treatment option.
Findings from some of the 56 studies examined for this review suggest that some medicines (dexamphetamine, bupropion, modafinil, methylphenidate and naltrexone) may be effective and suitable for some people in some circumstances, particularly when pharmacotherapy forms part of a comprehensive and individualised treatment plan, and are prescribed within a quality use of medicines framework. Each of these medicines showed a good safety profile with amphetamine users in the trials reviewed.
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 number of medicines that should be avoided because they have been shown to be harmful to use with methamphetamine users.
Additional research, particularly among Australian ATS users, is still required to understand the role of pharmacotherapy among people who are ATS-dependent, and to further identify how best the medicines that show promise can be appropriately prescribed.
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Kenny, P., Harney, A., Lee, N.K., & Pennay, A. (2011). Treatment utilization and barriers to treatment: results of a survey of dependent methamphetamine users. Substance Abuse Treatment, Prevention and Policy, 6(1): 3.
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Kongsakon, R., Papadopoulos, K.I. & Saguansiritham, R. (2005). Mirtazapine in amphetamine detoxification: a placebo-controlled pilot study. International Clinical Psychopharmacology, 20(5): 253–256.
Kypri, K., Langley, J.D., Saunders, J.B. & Cashell-Smith, M.L. (2007). Assessment may s for amphetamine-type stimulant u conceal therapeutic benefit: findings from a randomized controlled trial for hazardous drinking. Addiction, 102(1): 62–70.
Lee, N., Pennay, A., Hester, R., McKetin, R., Nielsen, S. & Ferris, J. (2013). A pilot randomised controlled trial of modafinil during acute methamphetamine withdrawal: feasibility, tolerability and clinical outcomes. Drug and Alcohol Review, 32(1): 88–95.
Lee, N.K. & Rawson, R.A. (2008). A systematic review of cognitive and behavioural therapies for methamphetamine dependence. Drug and Alcohol Review, 27(3): 309–317.
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Llorens Cortes, C., Pollard, H. & Schwartz, J.C. (1979). Localization of opiate receptors in substantia nigra evidence by lesion studies. Neuroscience Letters, 12(2–3): 165–170.
Longo, M., Wickes, W., Smout, M., Harrison, S., Cahill, S. & White, J.M. (2010). Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence. Addiction, 105(1): 146–154.
Majumder, I. & White, J. (2012). Pharmacology of amphetamine-type stimulants and implications for harms and responses. In S. Allsop & N. Lee (eds), Perspectives on Amphetamine-type Stimulants. Melbourne: IP Communications, pp. 21–32.
Martell, B.A., Orson, F.M., Poling, J., Mitchell, E., Rossen, R.D., Gardner, T. & Kosten, T.R. (2009). Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Archives of General Psychiatry, 66(10): 1116–1123.
Mattick, R.P., Breen, C., Kimber, J. & Davoli, M. (2009). Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database of Systematic Reviews, 2009(3): CD002209 [online].
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McGregor, C., Srisurapanont, M., Mitchell, A., Wickes, W. & White, J.M. (2008). Symptoms and sleep patterns during inpatient treatment of methamphetamine withdrawal: a comparison of mirtazapine and modafinil with treatment as usual. Journal of Substance Abuse Treatment, 35(3): 334–342.
McKetin, R., McLaren, J. & Kelly, E. (2005). The Sydney Methamphetamine Market: patterns of supply, use, personal harms and social consequences. (National Drug Law Enforcement Research Fund Monograph Series, no. 13.) Melbourne: Australasian Centre for Policing Research.
McKetin, R., McLaren, J., Kelly, E., Hall, W. & Hickman, M. (2005). Estimating the Number of Regular and Dependent Methamphetamine Users in Australia. (NDARC Technical Report no. 230.) Sydney: National Drug and Alcohol Research Centre.
McKetin, R., McLaren, J., Lubman, D.I. & Hides, L. (2006). The prevalence of psychotic symptoms among methamphetamine users. Addiction, 101(10): 1473–1478.
McKetin, R., Najman, J.M., Baker, A., Lubman, D.I., Dawe, S. et al. (2012). Evaluating the impact of community‐based treatment options on methamphetamine use: findings from the Methamphetamine Treatment Evaluation Study (MATES). Addiction, 107(11): 1998–2008.
McKetin, R., Ross, J., Kelly, E., Baker, A., Lee, N., Lubman, D.I. & Mattick, R. (2008). Characteristics and harms associated with injecting versus smoking methamphetamine among methamphetamine treatment entrants. Drug and Alcohol Review, 27(3): 277–285.
Meredith, C.W., Jaffe, C., Cherrier, M., Robinson, J.P., Malte, C.A. et al. (2009). Open trial of injectable risperidone for methamphetamine dependence. Journal of Addiction Medicine, 3(2): 55–65.
Meredith, C.W., Jaffe, C., Yanasak, E., Cherrier, M. & Saxon, A.J. (2007). An open-label pilot study of risperidone in the treatment of methamphetamine dependence. Journal of Psychoactive Drugs, 39(2): 167–172.
Miles, S.W., Sheridan, J., Russell, B., Kydd, R., Wheeler, A. et al. (2013). Extended-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction, 108(7): 1279–1286.
Miller, M.L., Moreno, A.Y., Aarde, S.M., Creehan, K.M., Vandewater, S.A. et al. (2012). A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. Biological Psychiatry, 73(8): 721–728.
Misra, L. & Kofoed, L. (1997). Risperidone treatment of methamphetamine psychosis. American Journal of Psychiatry, 154(8): 1170.
Misra, L.K., Kofoed, L., Oesterheld, J.R. & Richards, G.A. (2000). Olanzapine treatment of methamphetamine psychosis. Journal of Clinical Psychopharmacology, 20(3): 393–394.
Moreno, A.Y., Mayorov, A.V. & Janda, K.D. (2011). Impact of distinct chemical structures for the development of a methamphetamine vaccine. Journal of the American Chemical Society, 133(17): 6587–6595.
Nejtek, V.A., Avila, M., Chen, L.A., Zielinski, T., Djokovic, M. et al. (2008). Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial. Journal of Clinical Psychiatry, 69(8): 1257–1266.
Ost, L.G. (2008). Efficacy of the third wave of behavioral therapies: a systematic review and meta-analysis. Behaviour Research and Therapy, 46(3): 296–321.
Padgett, C.L. & Slesinger, P.A. (2010). GABA receptor coupling to G-proteins and ion channels. Advances in Pharmacology, 58: 123–147.
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Pennay, A.E. & Lee, N.K. (2009). Barriers to methamphetamine withdrawal treatment in Australia: findings from a survey of AOD service providers. Drug and Alcohol Review, 28(6): 636–640.
Potts, H.W.W. (2012). Meta-narrative review. Paper presented at the 5th ESRC [Economic & Social Research Council] Research Methods Festival, Oxford, July 2012.
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Rawson, R.A., Marinelli-Casey, P., Anglin, M.D., Dickow, A., Frazier, Y. et al. (2004). A multi-site comparison of psychosocial approaches for the treatment of methamphetamine dependence. Addiction, 99(6): 708–717.
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Rose, M.E. & Grant, J.E. (2008). Pharmacotherapy for methamphetamine dependence: a review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions. Annals of Clinical Psychiatry, 20(3): 145–155.
Salo, R., Nordahl, T.E., Galloway, G.P., Moore, C.D., Waters, C. & Leamon, M.H. (2009). Drug abstinence and cognitive control in methamphetamine-dependent individuals. Journal of Substance Abuse Treatment, 37(3): 292–297.
Shearer, J., Darke, S., Rodgers, C., Slade, T., van Beek, I. et al. (2009). A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction, 104(2): 224–233.
Shearer, J., Wodak, A., Mattick, R.P., Van Beek, I., Lewis, J., Hall, W. & Dolan, K. (2001). Pilot randomized controlled study of dexamphetamine substitution for amphetamine dependence. Addiction, 96(9): 1289–1296.
Shoptaw, S., Heinzerling, K.G., Rotheram-Fuller, E., Steward, T., Wang, J. et al. (2008). Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 96(3): 222–232.
Shoptaw, S., Huber, A., Peck, J., Yang, X., Liu, J. et al. (2006). Randomized, placebo-controlled trial of sertraline and contingency management for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 85(1): 12–18.
Shoptaw, S.J., Kao, U., Heinzerling, K. & Ling, W. (2009). Treatment for amphetamine withdrawal. Cochrane Database of Systematic Reviews, 2009(2): CD003021 [online].
Srisurapanont, M., Jarusuraisin, N. & Jittiwutikan, J. (1999). Amphetamine withdrawal: II. A placebo-controlled, randomised, double-blind study of amineptine treatment. Australian and New Zealand Journal of Psychiatry, 33(1): 94–98.
Srisurapanont, M., Jarusuraisin, N. & Kittirattanapaiboon, P. (2001). Treatment for amphetamine withdrawal. Cochrane Database of Systematic Reviews, 2001(4): CD003021 [online].
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Sulaiman, A.H., Gill, J.S., Said, M.A., Habil, M.H., Zainal, N.Z. & Guan, N.C. (2012). An open-label study of aripiprazole for methamphetamine induced psychosis. Bulletin of Clinical Psychopharmacology, 22(2): 121–129.
Swanson, A., Shoptaw, S. & Heinzerling, K.G. (2011). Varenicline for the treatment of methamphetamine dependence: a pilot study. Paper presented at the 73rd Annual Scientific Meeting of the College on Problems of Drug Dependence, Hollywood, Florida, June 2011.
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Urschel, H.C., Hanselka, L.L. & Baron, M. (2011). A controlled trial of flumazenil and gabapentin for initial treatment of methylamphetamine dependence. Journal of Psychopharmacology, 25(2): 254–262.
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Studies included in the systematic review
Akhondzadeh, S. & Hampa, A.D. (2005). Topiramate prevents ecstasy consumption: a case
report. Fundamental and Clinical Pharmacology, 19(5): 601–602.
Anderson, A.L., Li, S-H., Biswas, K., McSherry, F., Holmes, T. et al. (2012). Modafinil for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 120(1–3): 135–141.
Arnold, K.K. & Yager, J. (2007). A case of unexpected and selective remission of a 20-year history of ephedrine dependence following treatment with low-dose aripiprazole. Journal of Clinical Psychiatry, 68(10): 1620–1621.
Batki, S.L., Moon, J., Bradley, M., Hersh, D., Smolar, S. et al. (1999). Fluoxetine in methamphetamine dependence — a controlled trial: a preliminary analysis. Paper presented at the 61st Annual Scientific Meeting of the College on Problems of Drug Dependence, Acapulco, Mexico, June 1999.
Batki, S.L., Moon, K., Delucchi, K., Hersh, D., Bradley, C. et al. (2001). Amlodipine treatment of methamphetamine dependence, a controlled outpatient trial: preliminary analysis. Paper presented at the 63rd Annual Meeting of the College on Problems of Drug Dependence, Scottsdale, Arizona, June 2001.
Brodie, J.D., Figueroa, E., Laska, E.M. & Dewey, S.L. (2005). Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. Synapse, 55(2): 122–125.
Brown, E.S. & Gabrielson, B. (2012). A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. Journal of Affective Disorders, 143(1–3): 257–260.
Camacho, A. & Stein, M.B. (2002). Modafinil for social phobia and amphetamine dependence. American Journal of Psychiatry, 159(11): 1947–1948.
Camacho, A., Ng, B. & Frye, M.A. (2010). Modafinil for bipolar depression with comorbid methamphetamine abuse. American Journal on Addictions, 19(2): 190–191.
Carnwath, T., Garvey, T. & Holland, M. (2002). The prescription of dexamphetamine to patients with schizophrenia and amphetamine dependence. Journal of Psychopharmacology, 16(4): 373–377.
Charnaud, B. & Griffiths, V. (1998). Levels of intravenous drug misuse among clients prescribed oral dexamphetamine or oral methadone: a comparison. Drug and Alcohol Dependence, 52(1): 79–84.
Coffin, P.O., Santos, G.M., Das, M., Santos, D.M., Huffaker, S. et al. (2013). Aripiprazole for the treatment of methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction, 108(4): 751–761.
Colfax, G.N., Santos, G.M., Das, M., Santos, D.M., Matheson, T. et al. (2011). Mirtazapine to reduce methamphetamine use: a randomized controlled trial. Archives of General Psychiatry, 68(11): 1168–1175.
Cruickshank, C.C., Montebello, M.E., Dyer, K.R., Quigley, A., Blaszczyk, J., Tomkins, S. & Shand, D. (2008). A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal. Drug and Alcohol Review, 27(3): 326–333.
Das, M., Santos, D., Matheson, T., Santos, G.M., Chu, P. et al. (2010). Feasibility and acceptability of a phase II randomized pharmacologic intervention for methamphetamine dependence in high-risk men who have sex with men. AIDS, 24(7): 991–1000.
Elkashef, A.M., Kahn, R., Yu, E., Iturriaga, E., Li, S-H. et al. (2012). Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. Addiction, 107(7): 1297–1306.
Elkashef, A.M., Rawson, R.A., Anderson, A.L., Li, S-H., Holmes, T. et al. (2008). Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology, 33(5): 1162–1170.
Fetter, J.C. (2005). Mirtazepine for MDMA-induced depression. American Journal on Addictions, 14(3): 300–301.
Galloway, G.P., Buscemi, R., Coyle, J.R., Flower, K., Siegrist, J.D. et al. (2011). A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clinical Pharmacology & Therapeutics, 89(2): 276–282.
Grant, J.E., Odlaug, B.L. & Kim, S.W. (2010). A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. European Neuropsychopharmacology, 20(11): 823–828.
Heinzerling, K.G., Shoptaw, S., Peck, J.A., Yang, X., Liu, J., Roll, J. & Ling, W. (2006). Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 85(3): 177–184.
Heinzerling, K.G., Swanson, A.N., Kim, S., Cederblom, L., Moe, A., Ling, W. & Shoptaw, S. (2010). Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 109(1–3): 20–29.
Hester, R., Lee, N.K., Pennay, A., Nielsen, S. & Ferris, J. (2010). The effects of modafinil treatment on neuropsychological and attentional bias performance during 7-day inpatient withdrawal from methamphetamine dependence. Experimental and Clinical Psychopharmacology, 18(6): 489–497.
s for amphetamine-type stimulant u Jayaram-Lindström, N., Hammarberg, A., Beck, O. & Franck, J. (2008). Naltrexone for the treatment of amphetamine dependence: a randomized, placebo-controlled trial. American Journal of Psychiatry, 165(11): 1442–1448.
Jayaram-Lindström, N., Wennberg, P., Beck, O. & Franck, J. (2005). An open clinical trial of naltrexone for amphetamine dependence: compliance and tolerability. Nordic Journal of Psychiatry, 59(3): 167–171.
Jittiwutikan, J, Srisurapanont, M, & Jarusuraisin, N. (1997). Amineptine in the treatment of amphetamine withdrawal: a placebo-controlled, randomised, double-blind study. Journal of the Medical Association of Thailand, 80(9): 587–592.
Johnson, B.A., Ait-Daoud, N., Elkashef, A.M., Smith, E.V., Kahn, R. et al. (2008). A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence. International Journal of Neuropsychopharmacology, 11(1): 1–14.
Kongsakon, R., Papadopoulos, K.I. & Saguansiritham, R. (2005). Mirtazapine in amphetamine detoxification: a placebo-controlled pilot study. International Clinical Psychopharmacology, 20(5): 253–256.
Lee, N.K., Pennay, A., Hester, R., McKetin, R., Nielsen, S. & Ferris, J. (2013). A pilot randomised controlled trial of modafinil during acute methamphetamine withdrawal: feasibility, tolerability and clinical outcomes. Drug and Alcohol Review, 32(1): 88–95.
Leelahanaj, T., Kongsakon, R. & Netrakom, P. (2005). A 4-week, double-blind comparison of olanzapine with haloperidol in the treatment of amphetamine psychosis. Journal of the Medical Association of Thailand, 88 (Suppl 3): S43–52.
Ling, W., Shoptaw, S., Hillhouse, M., Bholat, M.A., Charuvastra, C. et al. (2012). Double-blind placebo-controlled evaluation of the PROMETATM protocol for methamphetamine dependence. Addiction, 107(2): 361–369.
Longo, M., Wickes, W., Smout, M., Harrison, S., Cahill, S. & White, J.M. (2010). Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence. Addiction, 105(1): 146–154.
McCann, D.J. & Li, S-H. (2012). A novel, nonbinary evaluation of success and failure reveals bupropion efficacy versus methamphetamine dependence: reanalysis of a multisite trial. CNS Neuroscience and Therapeutics, 18(5): 414–418.
McElhiney, M.C., Rabkin, J.G., Rabkin, R. & Nunes, E.V. (2009). Provigil (modafinil) plus cognitive behavioral therapy for methamphetamine use in HIV+ gay men: a pilot study. American Journal of Drug and Alcohol Abuse, 35(1): 34–37.
McGaugh, J., Mancino, M.J., Feldman, Z., Chopra, M.P., Gentry, W.B., Cargile, C. & Oliveto, A. (2009). Open-label pilot study of modafinil for methamphetamine dependence. Journal of Clinical Psychopharmacology, 29(5): 488–491.
McGregor, C., Srisurapanont, M., Mitchell, A., Wickes, W. & White, J.M. (2008). Symptoms and sleep patterns during inpatient treatment of methamphetamine withdrawal: a comparison of mirtazapine and modafinil with treatment as usual. Journal of Substance Abuse Treatment, 35(3): 334–342.
Meredith, C.W., Jaffe, C., Cherrier, M., Robinson, J.P., Malte, C.A. et al. (2009). Open trial of injectable risperidone for methamphetamine dependence. Journal of Addiction Medicine, 3(2): 55–65.
Meredith, C.W., Jaffe, C., Yanasak, E., Cherrier, M. & Saxon, A.J. (2007). An open-label pilot study of risperidone in the treatment of methamphetamine dependence. Journal of Psychoactive Drugs, 39(2): 167–172.
Merrill, J., McBride, A., Pates, R., Peters, L., Tetlow, A. et al. (2005). Dexamphetamine substitution as a treatment of amphetamine dependence: a two-centre randomised controlled trial. Drugs: Education, Prevention and Policy, 12(Suppl. 1): 94–97.
Miles, S.W., Sheridan, J., Russell, B., Kydd, R., Wheeler, A. et al. (2013). Extended-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction, 108(7): 1279–1286.
Misra, L., Kofoed, L., Oesterheld, J.R. & Richards, G.A. (2000). Olanzapine treatment of methamphetamine psychosis. Journal of Clinical Psychopharmacology, 20(3): 393–394.
Nejtek, V.A., Avila, M., Chen, L.A., Zielinski, T., Djokovic, M. et al. (2008). Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial. Journal of Clinical Psychiatry, 69(8): 1257–1266.
Shearer, J., Darke, S., Rodgers, C., Slade, T., van Beek, I. et al. (2009). A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction, 104(2): 224–233.
Shearer, J., Wodak, A., Mattick, R.P., Van Beek, I., Lewis, J., Hall, W. & Dolan, K. (2001). Pilot randomized controlled study of dexamphetamine substitution for amphetamine dependence. Addiction, 96(9): 1289–1296.
Shoptaw, S., Heinzerling, K.G., Rotheram-Fuller, E., Steward, T., Wang, J. et al. (2008). Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 96(3): 222–232.
Shoptaw, S., Huber, A., Peck, J., Yang, X., Liu, J. et al. (2006). Randomized, placebo-controlled trial of sertraline and contingency management for the treatment of methamphetamine dependence. Drug and Alcohol Dependence, 85(1): 12–18.
Shoptaw, S.J., Kao, U. & Ling, W. (2009). Treatment for amphetamine psychosis. Cochrane Database of Systematic Reviews, 2009(1): CD003026 [online].
Shoptaw, S.J., Kao, U., Heinzerling, K. & Ling, W. (2009). Treatment for amphetamine withdrawal. Cochrane Database of Systematic Reviews, 2009(2): CD003021 [online].
Srisurapanont, M., Jarusuraisin, N. & Jittiwutikan, J. (1999). Amphetamine withdrawal: II. A placebo-controlled, randomised, double-blind study of amineptine treatment. s for amphetamine-type stimulant u Australian and New Zealand Journal of Psychiatry, 33(1): 94–98.
Srisurapanont, M., Jarusuraisin, N. & Kittirattanapaiboon, P. (2001). Treatment for amphetamine withdrawal. Cochrane Database of Systematic Reviews, 2001(4): CD003021.
Sulaiman, A.H., Gill, J.S., Said, M.A., Habil, M.H., Zainal, N.Z. & Guan, N.C. (2012). An open-label study of aripiprazole for methamphetamine induced psychosis. Bulletin of Clinical Psychopharmacology, 22(2): 121–129.
Swanson, A., Shoptaw, S. & Heinzerling, K.G. (2011). Varenicline for the treatment of methamphetamine dependence: a pilot study. Paper presented at the 73rd Annual Scientific Meeting of the College on Problems of Drug Dependence, Hollywood, Florida, June 2011.
Tiihonen, J., Kuoppasalmi, K., Fohr, J., Tuomola, P., Kuikanmaki, O. et al. (2007). A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. American Journal of Psychiatry, 164(1): 160–162.
Urschel, H.C., Hanselka, L.L. & Baron, M. (2011). A controlled trial of flumazenil and gabapentin for initial treatment of methylamphetamine dependence. Journal of Psychopharmacology, 25(2): 254–262.
Urschel, H.C., Hanselka, L.L., Gromov, I., White, L. & Baron, M. (2007). Open-label study of a proprietary treatment program targeting type A gamma-aminobutyric acid receptor dysregulation in methamphetamine dependence. Mayo Clinic Proceedings, 82(10): 1170–1178.
White, R. (2000). Dexamphetamine substitution in the treatment of amphetamine abuse: an initial investigation. Addiction, 95(2): 229–238.
White, R., Thompson, M., Windsor, D., Walsh, M., Cox, D. & Charnaud, B. (2006). Dexamphetamine substitute-prescribing in pregnancy: a 10-year retrospective audit. Journal of Substance Use, 11(3): 205–216.
Zorick, T., Sugar, C.A., Hellemann, G., Shoptaw, S. & London, E.D. (2011). Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. Drug and Alcohol Dependence, 118(2–3): 500–503.
Appendix: Summary tables
Amphetamine withdrawal
Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Lee, N. et al. (2013). Modafinil 19 dependent methamphetamine Modafinil or placebo Well-conducted pilot A pilot randomised users (inpatients) who had used crushed in capsules for A range of clinical measures including: retention in treatment double-blind study, but small controlled trial methamphetamine in the 48 hours seven days (200 mg of in days; severity of withdrawal measured by Amphetamine sample size.
prior to recruitment and not depend- modafinil or matching Withdrawal Questionnaire (AWQ), Amphetamine Cessation Cohort were not daily ent on substances other than meth- placebo for days 1–5, and Symptoms Assessment (ACSA), Amphetamine Selective users but had been amphetamine, cannabis and nicotine Severity Assessment (ASSA); craving measured by participant- using for more than to titrate the dose before rated visual analogue scale, St Mary's Hospital Sleep six years on average feasibility, tolerability Questionnaire; and physiological measures included blood and were al injectors. Mean age: 34.3 years pressure, heart and respiration rates.
This is similar to, but outcomes. Drug Mean years of methamphetamine slightly less severe than, and Alcohol Review, use: approx. 6.5 years a large cohort of meth- 32(1): 88–95.
Mean use in last month: approx. Due to low power, there were no significant differences amphetamine users in between groups on any of the measures. There were no treatment reported by adverse events or side effects reported.
% injectors: not reported McKetin et al. (2012).
Randomised to modafinil (n=9) or placebo (n=10) Hester et al. (2010).
Hester, R. et al. 19 dependent methamphetamine Modafinil or placebo Well-conducted pilot (2010). The effects users (inpatients) who had used crushed in capsules for Neuropsychological test battery including: literacy (National double-blind study, but small methamphetamine in the 48 seven days (200 mg of Adult Reading Test); verbal and visual memory (Rey Auditory hours prior to recruitment and not modafinil or matching Verbal Learning test (RAVLT) and Rey Complex Figure test low follow-up for neuropsychological dependent on substances other placebo for days 1–5, and (RCFT)); working memory (Digit Span test, Psychomotor speed RCT (pilot) neuropsychological and attentional bias than methamphetamine, cannabis — Digit–Symbol Substitution test); executive function (Con- testing. Inpatient performance during to titrate the dose before trolled Oral Word Association test (COWAT), Trail Making test, 13 of the 19 eligible patients Stroop test, methamphetamine word emotional Stroop task).
underwent neuropsychological assessment at both baseline and Treatment was associated with a significant improvement in Experimental immediate verbal memory recall and a non-significant trend and Clinical toward improvement on executive function and delayed Mean age: 34.3 years memory tasks. No benefit was seen for measures of verbal 18(6): 489–497.
Mean years of methamphetamine learning, visual memory, processing speed, or verbal fluency. use: approx. 6.5 years All participants showed a significant attentional bias for Appendix: Summary tables methamphetamine-related stimuli on the emotional Stroop Mean use in last month: approx. task. The magnitude of bias predicted both retention in treatment and relapse potential at follow-up but was not % injectors: not reported significantly ameliorated by modafinil treatment. While non- Randomised to modafinil (n=9) or significant, the effect sizes of modafinil-related improvements in executive function and memory were consistent with those found in more robustly powered studies of cognitive benefits in attention-deficit hyperactivity disorder and schizophrenia.
Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
McGregor, C. et al. Mirtazapine, 49 dependent methamphetamine Modafinil (400 mg/ Pilot open-label study, s for amphetamine-type stimulant u (2008). Symptoms users (inpatients) day) and mirtazapine Severity of Dependence Scale; Amphetamine Cessation double-blind small sample size. No and sleep patterns (60 mg/day for up to 10 Symptoms Assessment (ACSA); Clinical Global Impression placebo control.
during inpatient days) were compared to Scale; Beck Depression Inventory II; St Mary's Hospital Sleep Cohort were near daily Mean age: 31.3 years a historical comparison users and had been Mean years of methamphetamine using for 10 years on pericyazine as per average. This is similar Mean use in last month: 23.6 days necessary (PRN) which was Modafinil and mirtazapine were well tolerated, producing to a large cohort of treatment as usual (TAU) minimal positive subjective effects and no discontinuation % injectors: not reported (2.5–10 mg/day) effects in this open-label study. Side effects were mild users in treatment treatment as usual. Randomised to mirtazapine (n=13) Symptomatic medications and transient. Both modafinil- and mirtazapine-treated reported by McKetin Journal of Substance or modafinil (n=14). A historical were available PRN for participants showed milder withdrawal symptoms compared et al. (2012).
Abuse Treatment, comparison group who had all groups (diazepam to TAU-treated participants; modafinil-treated participants 35(3): 334–342.
received treatment as usual (TAU) (5–10 mg) for anxiety, had a milder withdrawal syndrome and less sleep disturbance either nitrazepam in comparison to mirtazapine.
(5–10 mg) or temazepam (10–20 mg) for insomnia, and non-opioid analgesia was administered for pain) Shoptaw, S.J. et al. Amineptine, A review of four randomised Two studies of amineptine Summary
High-quality Cochrane (2009). Treatment mirtazapine controlled trials involving 125 and two of mirtazapine Two studies found that amineptine significantly reduced compared to placebo discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or Cochrane Database craving compared to placebo. The benefits of mirtazapine of Systematic over placebo for reducing amphetamine withdrawal symptoms Reviews, 2009(2): were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with United States of amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms.
Appendix: Summary tables Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
Cruickshank, C.C. Mirtazapine 31 dependent methamphetamine Mirtazapine 15 mg or s for amphetamine-type stimulant u users (outpatients) who had used placebo on the first A range of clinical measures including: Treatment retention; double-blind pilot study, but methamphetamine in the 72 hours two nights and 30 mg Amphetamine Cessation Symptoms Assessment (ACSA); small sample size controlled trial of prior to recruitment and not at mirtazapine nocte for Athens Insomnia Scale (AIS–5); Brief Symptom Inventory (BSI) and high drop-out mirtazapine for the significant risk of withdrawal from a further 12 nights. subscale BSI–GSI; Depression–Anxiety–Stress Scale (DASS); (52% completed the Medications were self- Severity of Dependence Scale; Opiate Treatment Index (OTI) two-week medication administered unsupervised, Drug Use subscale.
withdrawal. Drug + five sessions of 45 mins completed the five- and Alcohol Review, Mean age: 31 years narrative therapy both week study). Difficult 27(3): 326–333.
Mean years of methamphetamine No significant differences between groups on any of the to assess any ceiling use: not reported measures. Adverse events not reported.
effects of added Mean use in last month: 22.4 days % injectors: 54.8%Randomised to receive mirtazapine (n=13) or placebo (n=18) Kongsakon, R. et al. Mirtazapine 20 dependent methamphetamine Mirtazapine 15–60 mg Small sample size, (2005). Mirtazapine users in a probation centre per day or placebo with Depression was measured using the Montgomery–Asberg unclear whether study an initial dose of 15 mg Depression rating scale (MADRS) and ATS withdrawal was double blinded.
detoxification: a Males n=20 (100%) and titrated according to symptoms measured by the Amphetamine Withdrawal placebo-controlled the participants' clinical Mean age: 24.3 years response over 14 days. International Clinical Mean years of methamphetamine Participants were followed Summary
up on days 3 & 14 after Most participants responded well to mirtazapine on the initial 20(5): 253–256.
Mean use in last month not initiation of treatment.
dose of 15 mg/day and very few required a higher dose of 30 mg/day. Mild adverse events, such as headache, sedation, nausea and vomiting, were reported. There were significant % injectors: not reported differences between the two treatment groups in total AWQ Randomised to mirtazapine (n=9) score changes at days 3 and 14. Significant improvements or placebo (n=11) in favour of mirtazapine were also seen in hyperarousal and anxiety at days 3 and 14. No significant differences were seen in depression scores within or between the groups.
Appendix: Summary tables Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
Srisurapanont, M. 44 methamphetamine-dependent Amineptine 300 mg Well-conducted pilot s for amphetamine-type stimulant u daily for 14 days (plus Amphetamine Withdrawal Questionnaire (AWQ); Clinical double-blind RCT with small sample lorazepam 0.5–1.5 mg/ Global Impression (CGI) Scale.
withdrawal: II. A day for 5–14 days as per Cohort was young; placebo-controlled, Mean age: 19 years necessary for anxiety) nearly all men with Mean years of methamphetamine No differences were observed between groups on AWQ total less than two years double-blind study score at either week 1 or week 2. But mean AWQ reversed Mean use in last month: not vegetative scores of the amineptine group were significantly results may not be lower than those of the placebo group at weeks 1 and 2. No generalisable to older Australian and New significant differences were found on any comparisons of users with longer Zealand Journal of Mean amphetamine-use duration: AWQ hyperarousal score, AWQ anxiety score and AWQ total histories of ATS use.
Psychiatry, 33(1): score, or CGI score at the end of week 1. Total CGI score was % injectors: not reported significantly lower for the amineptine group than for those of Randomised to amineptine (n=22) the placebo group at week 2. Although the discontinuation or placebo (n=22) rate due to dissatisfaction with treatment in the amineptine group (1/21) was much lower than that of placebo group (6/22), those rates were not significantly different.
Srisurapanont, M. et A review of two randomised Two studies of amineptine Summary
High-quality Cochrane al. (2001). Treatment controlled trials involving 74 compared to placebo Both studies showed some benefits for discontinuation rate review, but minimally and global state, as measured by CGI, but no direct benefit withdrawal. Cochrane of amineptine on amphetamine withdrawal symptoms. The Database of results on amphetamine withdrawal symptoms and craving Systematic Reviews, came from only one study each.
Jittiwutikan, J. et al. Amineptine 30 dependent oral amphetamine- Amineptine 300 mg/ Well-conducted but (1997). Amineptine using inpatients, with DSM–IV day titrated over the first Stimulant withdrawal symptoms: Questionnaire for Evaluating double-blind small RCT.
in the treatment amphetamine withdrawal five days and matching Cocaine Craving and Related Responses (QECCRR); craving All participants used placebo for 14 days (a visual analogue scale measuring four domains of craving, oral amphetamine, depressed mood, no energy and feeling sick); and effects of were young, nearly placebo-controlled, Mean age: 18.5 years treatment (Clinical Global Impression scale — CGI).
randomised, double- Mean months of use: 23.6 been using for less blind study. Journal Appendix: Summary tables % injectors: not reported than two years which of the Medical Amineptine improved self-reported depression and overall limits generalising Association of Randomised to either amineptine clinical presentation, but had no effect on craving when findings to longer- Thailand, 80(9): n=15 or placebo n=15 compared to placebo. Six of the eight who dropped out did term, heavier users of so for lack of efficacy — n=1 amineptine and n=5 placebo — which is a trend but not significant.
Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
60 dependent methamphetamine Participants received either Measures
s for amphetamine-type stimulant u et al. (2011). A users (outpatients) 60 mg d-AMP sustained- Number of methamphetamine-negative urine drug screens double-blind double-blind RCT, randomized, placebo- (d-AMP) release (SR) or placebo (collected twice weekly); self-reported methamphetamine use multi-site originally designed controlled trial of daily for eight weeks. This (Time Line Follow Back — TLFB); Amphetamine Withdrawal to examine treatment sustained-release Mean age: 37 years was given as a single dose Questionnaire (AWQ); The Desire for Speed Questionnaire for dependence but dextroamphetamine Mean years of use: 2 years on the first day and as (visual analogue craving scale); medication adherence measures withdrawal for treatment of two equally divided doses Mean use in last month: approx. on subsequent days.
addiction. Clinical All received 50-min. Pharmacology & % injectors: not reported (80% manual-based individual The dexamphetamine group reported significantly less craving Cohort were not daily Therapeutics, 89(2): active group and 67% placebo and fewer withdrawal symptoms. No serious adverse events group smoked MA primarily) motivational enhancement users and had been therapy sessions once a occurred during the trial, but n=30 reported mild adverse using for an average United States of Randomised to either placebo week for nine weeks.
of two years.
(n=30) or d-AMP (n=30) Longo, M. et al. 49 dependent methamphetamine- The study period (2010). Randomized using outpatients who had used comprised an initial Self-reported methamphetamine use and hair analysis double-blind, Australian double- controlled trial of methamphetamine on three or stabilisation period of at three time-points (baseline, the end of maintenance, blind RCT, originally more days per week over the up to 14 days, with an and follow-up); degree of dependence over time (Leeds designed to examine previous 12 months. 86% were initial dose of 20 mg/ Dependence Questionnaire — LDQ); treatment retention.
dexamphetamine for the treatment of day of a SR formulation of dexamphetamine dependence but also increased by 10 mg Dexamphetamine was well tolerated and safe under measured withdrawal Addiction, 105(1): Mean age: 31.9 years daily as required until pharmacist-supervised, daily dosing conditions. There was Mean years of methamphetamine stabilised or in receipt of a trend toward greater reduction of reduced withdrawal Small sample size and use: not reported a maximum of 110 mg/ symptom severity during stabilisation in the dexamphetamine high rate of attrition Mean use in last month: not day for 90 days. All from the trial among participants underwent the placebo group.
stabilisation (withdrawal Mean age first use: approx. 20 assessed by AWQ), Unclear how long with the placebo group Median use in past 3 months: 69 receiving increasing numbers of placebo the participants had been using at the beginning of the trial.
Appendix: Summary tables Randomised to receive either Plus all participants dexamphetamine (n=23) or placebo received four sessions (n=26) of cognitive behaviour therapy (CBT) for amphetamine users.
Treatment for amphetamine dependence
Dexamphetamine and other psychostimulants
s for amphetamine-type stimulant u Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
60 dependent methamphetamine Participants received either 60 mg Measures
d-AMP SR or placebo daily for Primary measure: Number of methamphetamine-negative double-blind RCT with a eight weeks. This was given as a sufficient sample urine drug screens (collected twice weekly).
single dose on the first day and size, reasonable controlled trial of Mean age: 37 years as two equally divided doses on Secondary measures: self-reported methamphetamine use sustained-release Mean 18.9 days of methampheta- subsequent days.
(TLFB); Amphetamine Withdrawal Questionnaire (AWQ); dextroamphetamine mine use in last 30 days The Desire for Speed Questionnaire (visual analogue craving All received 50-min., manual- scale); and medication adherence self-report.
for treatment of Randomised to dextroamphetamine based, individual motivational follow-up rate.
(n=30) or placebo (n=30) enhancement therapy sessions addiction. Clinical once a week for nine weeks.
There were no significant differences between groups Pharmacology on methamphetamine use measures (self-reported & Therapeutics, methamphetamine using days, number of methamphetamine- 89(2): 276–282.
free urine samples), but the dextroamphetamine group United States of reported significantly less craving and fewer withdrawal symptoms. No serious adverse events occurred during the trial. There was no significant difference between groups on medication adherence or attendance at psychosocial treatment sessions. Around 75% of both groups took the dispensed medication.
Appendix: Summary tables Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
40 dependent methamphetamine The study period comprised an A well-conducted, s for amphetamine-type stimulant u users who had used methampheta- initial stabilisation period of up Self-reported methamphetamine use and hair analysis double-blind, Australian mine on three or more days per to 14 days, with an initial dose of at three time-points (baseline, the end of maintenance, double-blind RCT. controlled trial of week over the previous 12 months. 20 mg/day of a SR formulation and follow-up); degree of dependence over time (Leeds Small sample size 86% were IV users of dexamphetamine increased by Dependence Questionnaire); treatment retention.
and high rate of 10 mg daily as required until stabi- attrition from the the treatment of lised or until the participant was in Summary
Mean age: 31.9 years receipt of a maximum of 110 mg/ Dexamphetamine was well tolerated and safe under placebo group.
Mean years of methamphetamine day for 90 days. All participants pharmacist-supervised, daily dosing conditions. Intention Addiction, 105(1): use: not reported underwent stabilisation (with- to treat (ITT) analysis showed that participants taking Mean use in last month: not drawal assessed by AWQ), with the dexamphetamine stayed in treatment significantly longer placebo group receiving increasing (86.3 days) compared to placebo (48.6 days).
numbers of placebo capsules.
Mean age first use: approx. 20 years Dexamphetamine increased treatment retention, reduced At the end of the maintenance degree of dependence and withdrawal symptom severity Median use in past 3 months: period, participants were tapered during stabilisation. Those on dexamphetamine were but also measured off the medication over one significantly less likely to drop out of the study (n=8/23) Randomised to receive either month in order to minimise than those in the placebo group (n=18/26) (P=0.040); 61% dexamphetamine (n=23) or placebo any withdrawal symptoms in the dexamphetamine group and 54% in the placebo group experienced. Participants were attended at least one CBT session (NS).
followed up two months after completing treatment.
Plus all participants received four sessions of CBT for amphetamine users.
47 amphetamine-using women Dexamphetamine substitution, with Measures
who were prescribed dexam- typical doses of an oral y adminis- Cigarette and alcohol use, outcome by prescription regime phetamine, 41 women who were tered elixir being between 30 mg and drug use.
data analysis cohort study but not amphetamine-using, and and 60 mg, is offered to pregnant relied on record two equivalent groups of heroin amphetamine users. There was an retrospective keeping of clinical users and members of the general emphasis on reducing the dose of There was a high rate of low birth-weight babies in both dexamphetamine through the preg- groups, which was not considered to be substantially nancy and an expectation that this related to prescribed dexamphetamine, as birth weights missing, although audit. Journal of can usual y be done at a faster rate were very similar in those not prescribed dexamphetamine. Mean age: 26.7 years Appendix: Summary tables Substance Use, than for a woman on methadone. There was no association demonstrated with duration of 11(3): 205–216.
Injecting use: 56.8% Thus, ideal y, patients are detoxified prescribing or maximum dose. ‘On-top' use was the best Mean years of methamphetamine before the third trimester.
predictor of adverse birth outcomes. The authors concluded use: not reported Pregnant heroin users are offered that dexamphetamine substitution should be initiated with comparison group caution and used as a last-line treatment. Clients should was opportunistic Mean use in last 30 days: not methadone as the treatment of be informed of possible risks, including those relating to choice, but dihydrocodeine is also used on an occasional basis.
continued use of street-drugs.
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
59 dependent amphetamine users, Random assignment to Level II RCT. A well-designed s for amphetamine-type stimulant u dexamphetamine tablets up to Standard questionnaires on drug use, physical and Blinding not trial but reporting 100 mg per day dispensed daily psychological health, social functioning and quality of life, by a pharmacist (maintenance offending behaviour, and satisfaction with treatment (no Mean age: not reported for four months, then taper for measure specified).
Small sample size Mean years of methamphetamine three months) plus best available use: not reported treatment (BATA), or BATA alone. Summary
Mean use in last 7 days: 19.3 g BATA consisted of providing There was no significant difference between groups on use literature on amphetamines; measures with both groups reporting reductions and no controlled trial. Randomised to dexamphetamine motivational interviewing (MI); difference in injecting behaviour between the groups. A trend Drugs: Education, n=32 or best available treatment drug use diary; discussion of cues, toward the reduction of polydrug use and improvements alone (BATA) n=27 Prevention coping and lapse management; in psychological health and significant improvement in the and Policy, advice on healthy lifestyles; harm dexamphetamine group on physical health indicators.
minimisation advice; referral for other supports; symptomatic prescribing for depression, anxiety and insomnia; and the possibility for inpatient detoxification if clinically indicated.
After randomisation, participants received weekly clinical appointments for four weeks, then fortnightly until seven months (end of dex. prescribing period).
41 dependent amphetamine users; All participants received al. (2001). Pilot 32% homosexual or bisexual men; psychological counselling. In Urine screens at baseline, 6 weeks and 12 weeks; self-reported double-blind study with a 95% injecting drug users addition, the treatment group amphetamine use (Opiate Treatment Index — OTI); Severity of RCT (pilot) were prescribed dexamphetamine Dependence Scale (SDS).
to a maximum daily supervised Mean age: 29 years oral dose of 60 mg. Induction substitution for Mean years of methamphetamine began at 20 mg, increasing by Non-significant reductions in street amphetamine use and 5 mg daily until a maximum amphetamine dependence were observed in both groups. relatively large dose was achieved. The dose was Treatment participants were significantly more likely to attend proportion of gay Appendix: Summary tables 31% shared injecting equipment in Addiction, 96(9): month prior to intake reduced in the final two weeks counselling. There was no significant difference between to a maximum dose of 40 mg at groups in amphetamine use. The severity of dependence were included.
Randomised to dex. plus reduced significantly more among the active treatment group counselling n=21 or counselling compared with controls at post-treatment but not follow-up. There were no reports of adverse events.
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
White, R. (2000). The standardised records of 220 Dexamphetamine was prescribed s for amphetamine-type stimulant u users receiving dexamphetamine exclusively in elixir form. Initial Ceasing illicit use; treatment retention.
prescriptions were examined dosing was based on self-reports data analysis retrospective retrospectively and cross-sectional of levels of use up to a maximum Summary
cohort study.
socio-demographic data and of 90 mg. The prescription was Oral and injecting users had similar outcomes, with injecting abuse: an initial longitudinal outcome data were continued until street-use ceased. users making more overall gains in treatment. Over half the obtained for 148 users. Injection sites were routinely injectors stopped injecting, more than one-third within two Addiction, 95(2): months of coming into treatment. Failure to stop injecting was related to shorter time in treatment. Variables predicting a good outcome differed between oral and intravenous users, although for both groups being female was associated with a slower change in drug-use behaviours, but a longer period in treatment. 13.6% (n=13) of injectors and 9.4% (n=5) of oral users relapsed into street-use after successfully stopping. Relapse occurred later with a median of 16.0 months for injecting users.
180 clients of a community Dose usually calculated as 1 g A well-conducted drug treatment service in the street amphetamine to 20 ml Demographic characteristics, age of first drug use, duration retrospective but low-level UK who were injecting heroin or dexamphetamine elixir — mean of use, duration of treatment, psychotic episodes, and level chart review retrospective amphetamine on a daily basis for at dose of dexamphetamine for the of injecting at discharge (assessed by visual observation of least six months prior to receiving amphetamine sample was 43 ml injection sites).
(range 15–75 ml) vs mean dose of not standardised, Males n=52 (87%) methadone of 44 ml (11–80 ml), (dexamphetamine), n=98 (82%) at 1 mg per ml elixir (dex. dose There were no differences between groups at the beginning negotiated with clients) of treatment. There were no differences in outcomes between the groups, including injecting rates, median Mean age: 28 years time in treatment, suggesting that amphetamine users on Drug and Alcohol dexamphetamine (32 years dexamphetamine maintenance did just as well as heroin users Dependence, on methadone.
52(1): 79–84.
Median years of injecting methamphetamine: 7 years (9 years injecting heroin for methadone group)Mean use in last 30 days: not Appendix: Summary tables reportedEither on methadone (n=120) or dexamphetamine elixir (n=60) Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
79 dependent amphetamine/ Methylphenidate (or a placebo Double-blind High-quality, s for amphetamine-type stimulant u methamphetamine users n=41 equivalent) 18 mg daily for the Urine drug screens for methamphetamine; previous and well-designed and Extended release from New Zealand (mainly smokers first week, 36 mg daily for the current substance use (Pompidou questionnaire); Severity conducted trial.
of methamphetamine) and n=38 second week, and 54 mg daily of Dependence Scale (SDS); methamphetamine craving Findings limited for treatment of from Finland (mainly injectors of for 20 weeks until the end of (visual analogue scale); alcohol use (Alcohol Use Disorders by high attrition the 22-week trial. Participants Identification Test — AUDIT); and adverse medication effects.
attended the clinics daily for Mean age: 37.5 years for Finland; Methylphenidate was no more effective than placebo in 35.3 years for New Zealand reducing the number of methamphetamine-positive urines Mean years of methamphetamine returned by participants or decreasing scores on the craving controlled trial. scale or SDS. There was a high attrition rate from the Addiction, 108(7): All participants returned study — only 34.2% completed 22 weeks, with the placebo methamphetamine-positive urine group having a significantly lower retention rate than the screens at baseline methylphenidate group. There was a decrease in mean SDS scores (–3.7 for methylphenidate vs –1.6 for placebo) and Randomised to methylphenidate craving scores (–21.2 for methylphenidate vs –13.3 for n=40 or placebo n=38 placebo) but neither reached statistical significance. Authors Participants had high scores on suggest high attrition could be due in part to the requirement severity of dependence (SDS) for daily clinic visits for dosing.
at baseline (mean 10.5 for methylphenidate group and 10 for placebo) Aripiprazole, 53 dependent amphetamine users Aripiprazole 15 mg/day A well-conducted Methylphenidate 18 mg/day for The primary outcome measure was the proportion of double-blind study with ITT the first week, 36 mg/day for the amphetamine-positive urine samples during pharmacological analysis but small Mean age: 32.2 years second week, and 54 mg/day methylphenidate, Mean years of methamphetamine use: approx. 14 years Equivalent gel capsule placebo Randomised to aripiprazole (n=19), Patients allocated to aripiprazole had significantly more for analysis.
methylphenidate (n=17) or placebo amphetamine-positive urine samples than did the placebo American Journal group. Those who received methylphenidate had significantly of Psychiatry, fewer amphetamine-positive urine samples than did the 164(1): 160–162.
placebo group. The trial was ceased after initial analysis Appendix: Summary tables reported aripiprazole significantly worsened symptoms. Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u 12 weeks of medication: modafinil methamphetamine users 200 mg/day, modafinil 400 mg/ Methamphetamine non-use weeks assessed by urine samples for Males n=124 (59%) methamphetamine metabolites; abstinence at termination of double-blind well conducted the treatment of All participants received treatment; Addiction Severity Index (ASI); Hamilton Depression Rating placebo- Mean age: 39 years standardised 90-minutes of CBT Scale (HAM–D); adverse events; Brief Substance Craving Scale; Clinical controlled group counselling three times per Global Impression Scale (CGI); HIV Risk-Taking Behaviour Scale.
Drug and Alcohol methamphetamine use in past week for 12 weeks.
Dependence, All participants received one session Participants in al three groups had an increase in methamphetamine- of motivational enhancement at free weeks over the duration of the study, with no differences between methamphetamine use: not United States of groups on methamphetamine non-use weeks overal or on maximum number of methamphetamine non-use days or on ‘terminal abstinence' Randomised to modafinil 200 at the completion of the study as assessed by urine screens.
mg daily (n=72), modafinil Participants who were compliant with modafinil dosing had a 400 mg daily (n=70), or longer duration of consecutive non-using days than less compliant participants and showed better study retention.
No differences between groups for ASI, CGI, craving, or HIV risk-taking behaviours.
Of the four serious adverse events that occurred during the study period, none was related to modafinil.
Appendix: Summary tables Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
Heinzerling, K.G. Twelve weeks of medication: A well-conducted s for amphetamine-type stimulant u methamphetamine users modafinil 200 mg per day (two Urine samples collected three times a week; ASI–Lite to measure the — double- 100 mg tablets per day taken in the severity of addiction-related problems in seven areas of functioning: blind, morning) for the first three days of medical; employment; drug use; alcohol use; legal; family/social; sample size, but Mean age: 39.1 years the study followed by an increase and psychiatric; Beck Depression Inventory (BDI); methamphetamine controlled controlled trial to 400 mg per day (four 100 mg craving measured weekly using a visual analogue scale; pill count for RCT of modafinil for methamphetamine use: tablets per day taken at one time the treatment of in the morning) until the last three Mean use in last month: days of the trial, when the dose was titrated down to 200 mg per There were no differences between the groups on drug use, retention, Drug and Alcohol day for the final three days.
depression or craving. There were no medication-related adverse events. Randomised to modafinil Dependence, Weekly individual CBT sessions Depressive symptoms decreased during the medication treatment period, n=34 or placebo n=37 during the medication phase of the but there were no significant differences between groups. Metham- United States of study plus contingency management phetamine cravings decreased but there were no significant differences (vouchers for goods and services for between groups. Participants in the modafinil group received on average methamphetamine-free urines … the $113 of the $537 possible from the contingency management interven- tion reinforcing methamphetamine-free urine drug screens, while par- maximum that could be earned for providing methamphetamine- and ticipants in the placebo group received $139 (t=–0.70, d.f.=69, p=0.49). metabolite-free urine samples at all Participants with baseline high-frequency of methamphetamine use were visits throughout the entire study more likely to have low CBT attendance in comparison with those with was $537 in vouchers).
low-baseline methamphetamine use (x2=3.8, d.f.=69, p=0.05).
McElhiney, M.C. et Modafinil 13 gay men n=11 (85%) HIV+ Twelve weeks of modafinil followed Measures
al. (2009). Provigil n=7 with DSM–IV stimulant by four weeks of placebo. Starting Urine drug screen; methamphetamine use self-report; Hamilton a Level III pilot abuse (54%) and n=6 DSM–IV modafinil dose was 50 mg/day Rating Scale for Depression (HAM–D); University of Minnesota blind within with small stimulant dependence (46%) for those taking HIV antiretroviral Cocaine Craving Scale; Obsessive Compulsive Drinking Scale adapted subjects sample. Analysis Males n=13 (100%) medications and 100 mg/day for others. The dose was increased Mean age: 38 (SD 6) years to 200 mg/day in the absence of Mean years of methampheta- clinical response and significant Results are provided for completers only. Six of the 10 completers men: a pilot study. mine use: not reported side effects.
showed a greater than 50% reduction in methamphetamine days per participants. Low American Journal Mean estimated duration The 16-week therapy component week. The authors concluded that modafinil appeared to be more dose of modafinil of Drug and of abuse or dependence: started with two weeks of twice- useful to patients with a diagnosis of abuse rather than dependence Alcohol Abuse, weekly sessions with a motivational and may be most effective as a short-term abstinence-induction other studies.
35(1): 34–37.
agent, which can then be discontinued. The addition of CBT to Appendix: Summary tables Mean use in last 30 days: enhancement emphasis followed United States of address sexual issues appears to promote treatment retention. Ten by weekly CBT sessions for the remaining 14 weeks.
participants (77%) completed the 16-week trial.
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
McGaugh, J. et al. Modafinil Participants were started on s for amphetamine-type stimulant u methamphetamine users modafinil 200 mg daily for the Urine screen and vital sign measure three times a week; self-reported open-label label pilot study first three days, then increased to amphetamine use weekly using analogue scales; weekly Hamilton label study.
of modafinil for 400 mg daily. They were maintained depression and anxiety scales (HAM–D/HAM–A), modafinil side Mean age: 45.3 years on modafinil for five weeks and then effects checklist.
mine dependence. observed for five days during week 6 Journal of Clinical methamphetamine use: not after modafinil was discontinued.
Weekly manual-driven, individu- Study showed the tolerability and safety of modafinil 400 mg/day cology, 29(5): Mean use in last 30 days: alised CBT for relapse prevention among a sample of eight methamphetamine-dependent outpatients. plus contingency management with Although anxiety is a potential side effect of modafinil, ratings on United States of monetary rewards in exchange for both the Hamilton anxiety and depression scales decreased over returning medication blister packs, the course of the study. The study was not designed to test the submitting urine samples thrice efficacy of modafinil for methamphetamine dependence, however weekly for analysis, and attending self-reported methamphetamine use decreased but amphetamine- cognitive behaviour therapy sessions. positive urine screens did not change. Scores on both the HAM–D and HAM–A decreased significantly.
Shearer, J. et al. Modafinil 200 mg/day dispensed (2009). A double- methamphetamine users weekly for 10 weeks using Self-reported ATS use: The Opiate Treatment Index (OTI) and double-blind study with a Males n=50 (62.5%) medication event monitoring 28-day drug use diaries; Brief Symptom Inventory (BSI); Severity of controlled trial system (MEMS) cap bottles to Dependence Scale (SDS); methamphetamine craving in the past week controlled Mean age: 35.9 years record unsupervised regimen on a100-mm visual analogue scale (VAS); weekly urine specimens (200 mg/day) for during treatment; adverse events.
methamphetamine use: All participants were offered a brief ITT analysis was four-session cognitive behavioural Addiction, 104(2): Mean use in last 28 days: intervention developed specifically There were no differences in methamphetamine abstinence, for methamphetamine users.
craving, severity of dependence, treatment retention or medication adherence. There was a non-significant trend for medication- Randomised to modafinil compliant participants to provide more methamphetamine-negative n=38 or placebo n=42 urine samples. Outcomes were better for methamphetamine-dependent participants with no other substance dependence and those who accessed counselling. The medication was well tolerated. Drop-out rate was very high (more than 60%).
Regardless of group allocation, each session of counselling attended during the 10-week treatment period reduced 28-day stimulant self- Appendix: Summary tables report by one day (95% CI: –1.7, –0.3) at post-treatment follow-up. Simply attending any form of counselling reduced 28-day self-report by six days (95% CI: –10.8, –1.8).
HIV-positive participants who were over-represented in the modafinil group had poorer methamphetamine use outcomes.
Number and description Intervention and
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u 30 men dependent Bupropion 150 mg and A well-conducted (2010). Feasibility methamphetamine users matching placebo taken Medication adherence – MEMS caps, self-reported adherence using the 4-day double-blind pilot study. Small and acceptability who had anal sex with daily for one week, Structured Self-Report; medication safety – weekly self-report, symptom-driven placebo- sample size. Good men in the past three increased to 300 mg from physical exams and safety laboratory monitoring were done at weeks 4, 8, study completion months while using week 2 to week 12, plus and 12 and classified according to Division of AIDS (DAIDS) Table for Grading weekly 30-min. CBT/MI Severity of Adult Adverse Experiences for HIV Prevention Trials Network. Drug intervention for counselling sessions for use, risks, depression using audio computer-assisted self-interview (ACASI) Males n=30 (100%) methamphetamine use, — frequency and route of administration of methamphetamine and other plus medication adherence drug use; AOD treatment; Severity of Dependence Scale (SDS); Center for Mean age: 35.7 years counselling by the study Epidemiologic Studies Depression Rating Scale (CES–D); sexual risk behaviour; who have sex with Mean years of use: not clinician (frequency not reasons for non-adherence; attitudes about trial participation.
men. AIDS, 24(7): reported, but possibly Mean use in last month: one-off) United States of less than 3 days a week Both groups showed improvements on all measures. There was no significant n=14 (42.5%); 3–7 days difference between the two groups in treatment completion, self-reported a week n=16 (57.5%) medication adherence (both groups over-estimated their medication adherence on self-report), reduction in methamphetamine-metabolite positive urine drug screens, sexual risk-taking behaviours, or depression. There were no serious bupropion (n=20) or adverse events from the medications. Ninety-six per cent of participants were highly satisfied or satisfied with study participation. Authors conclude that the study demonstrates the feasibility of enrolling and retaining a typically hard-to-engage group of methamphetamine users into treatment.
Ninety per cent completed the trial: 89% of monthly ACASIs were completed; 81% of study visits were attended; and 81% of urine samples were collected. Adherence by MEMS cap was 60% and by self-report was 81% and did not differ significantly by treatment assignment.
The median number of positive urine samples was 5.5 out of a possible 11 (50%). Participants in both arms reported similar non-significant decline in the median number of sex partners.
No serious adverse events occurred and there were no significant differences in adverse events by treatment assignment.
Appendix: Summary tables Number and description Intervention and
comparison if relevant
Primary outcomes including measures used
Film-coated sustained- A well-conducted, s for amphetamine-type stimulant u methamphetamine users release bupropion 150 mg Percentage of abstinence was measured by urine drug screens three times a double-blind double-blind RCT.
Males n=101 (67%) or matched placebo once week for methamphetamine; Brief Substance Craving Scale (BSCS); Hamilton the treatment of daily for three days, then Depression Scale (HAM–D); Timeline follow-back; Addiction Severity Index Mean age: 36 years 300 mg daily (one tablet (ASI–Lite); adherence was assessed by weekly tablet count.
mine dependence. Mean years of use: twice a day) for 11 weeks, then dose was reduced to macology, 33(5): Mean use in last month: 150 mg daily on the last There was no significant difference between groups on probability of a non- ≤18 days n=71 (47%); three days of the 12-week use week, but subgroup analysis showed that bupropion had a significant United States of and >18 days n=80 effect, compared to placebo, among male patients who had a lower level of All participants received methamphetamine use at baseline. The authors concluded that bupropion, in combination with behavioural group therapy, was effective for increasing 90 mins of manualised, the number of weeks of abstinence in participants with low-to-moderate buproprion n=79 or group-based CBT three methamphetamine dependence in male patients.
times a week (Matrix Model) for 12 weeks.
Sustained-release Li, S-H. (2012). A methamphetamine users bupropion 150 mg Primary outcome assessment was urine drug screens three times per week; Brief double-blind, reanalysis of a novel, nonbinary Males n=101 (67%) and matched placebo. Substance Craving Scale (BSCS); Hamilton Depression Scale (HAM–D); self- Participants received doses report of methamphetamine use (TLFB); Addiction Severity Index (ASI–Lite).
double-blind RCT Mean age: 36 years of bupropion 150 mg (Elkashef et al. SR or placebo, once methamphetamine use: daily for three days, then This study re-analysed data from Elkashef et al. 2008. The original study failed for success have increased to 300 mg daily to demonstrate an effect for bupropion, but found some subgroups benefited limited clinical Mean use in last 30 (one tablet twice a day) from bupropion. The current paper used a different method of analysis to for about 11 weeks of demonstrate a positive effect of bupropion based on FDA evaluations of treatment, until the final medicine to treat alcohol and tobacco dependence.
multisite trial. dose taper. The dose was Throughout the course of the study, the success rate in the bupropion group CNS Neuroscience bupropion (n=79) or reduced to 150 mg daily seemed to increase in a biphasic fashion, with a plateau at 11% (9/79) from and Therapeutics, on the last three days of study weeks 4–6, which then increased steadily to 20% (16/79). In the placebo 18(5): 414–418.
the 12-week treatment group, only 7% (5/72) were able to achieve two or more weeks of EOSA.
(Also see Elkashef period. Adherence was Of the 16 treatment participants who did attain two or more weeks assessed by weekly tablet of methamphetamine abstinence during the trial (range 2–12 weeks above for original during the trial), the only factor that was significantly associated with a Appendix: Summary tables All participants received ‘successful outcome' with bupropion treatment was the self-reported level United States of 90 mins of manualised, of methamphetamine use during the 30 days immediately before screening; group-based CBT three the proportion of ‘treatment successes' reporting 18 days or less of baseline times a week (Matrix methamphetamine use (69%) was significantly greater than the proportion of Model) for 12 weeks.
treatment failures reporting this level of baseline use (40%; P=0.04).
Number and description Intervention and
comparison if relevant
Primary outcomes including measures used
Slow-release bupropion s for amphetamine-type stimulant u methamphetamine users 150 mg (or placebo) per Methamphetamine use as assessed via urine drug screens; treatment retention; double-blind well-conducted recruited from three sites, day for days 1–3 of the depressive symptoms (Beck Depression Inventory — BDI); methamphetamine predominantly smokers first week followed by an cravings (visual analogue scale); and adverse events.
completion rates controlled trial of methamphetamine increase to 300 mg per (around 35%).
of bupropion for day (one 150 mg capsule the treatment of taken twice daily) until There were no significant effects for bupropion relative to placebo on Males n=22 (61%) week 12 when the dose methamphetamine use verified by urine drug screens, for reducing the severity Mean age: 34.6 years was decreased to 150 mg of depressive symptoms or methamphetamine cravings, or on study retention. Drug and Alcohol of bupropion SR for the In a post hoc analysis, there was a statistically significant effect of bupropion Dependence, methamphetamine use: treatment on methamphetamine use and completion rates among participants 96(3): 222–232.
Weekly individual CBT with lighter (0–2 methamphetamine-positive urines), but not heavier (3–6 United States of Mean use in last 30 sessions for 12 weeks methamphetamine-positive urines) use at baseline. Bupropion treatment was also associated with significantly reduced cigarette smoking, by almost Non-cash vouchers for five cigarettes per day. No significant differences in depression scores, which methamphetamine-free decreased among both groups. No significant differences in methamphetamine bupropion (n=36) or urine screens (max. value craving, which decreased among both groups. No differences in the number of counselling sessions attended (5/12 for bupropion, 4/12 for placebo). No treatment-related serious adverse effects.
Appendix: Summary tables Intervention and
Number and description of participants
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Grant, J.E. et al. 31 dependent methamphetamine users 600 mg/day NAC plus (2010). A double- 50 mg/day naltrexone Penn Craving Scale; frequency of methamphetamine use; urine double-blind, conducted blind, placebo-control- (NAC) plus for two weeks, then drug screen; Clinical Global Impression (Severity) scale (CGI); led study of N-acetyl naltrexone Mean age: 36.6 years 1200 mg/day NAC plus Hamilton Rating Scale for Depression (HAM–D); Hamilton cysteine plus naltrex- Mean age first used methamphetamine: 100 mg/day naltrexone Rating Scale for Anxiety (HAM–A); Sheehan Disability Scale one for methampheta- for two weeks, and (SDS); the Quality of Life Inventory (QoLI).
mine dependence. Mean years of methamphetamine use: not 1800 mg/day NAC plus 150 mg/day naltrexone for two weeks, and to There were no differences between groups on any measures. Mean days used methamphetamine in past 20(11): 823–828.
2400 mg/day NAC plus The authors concluded that adding naltrexone to NAC did not two weeks: 7.18 days 200 mg/day naltrexone significantly reduce craving among non-treatment-seeking United States of Randomised to NAC + naltrexone (n=14) or for the final two weeks NAC + placebo (n=17) Jayaram-Lindström, Naltrexone 20 dependent methamphetamine users who 50 mg naltrexone daily, had used amphetamine at least 12 days in dispensed weekly for Self-reported amphetamine use (TLFB); Craving Visual Analog the last 12 weeks 12 weeks, plus 30 mins Scale (VAS); weekly urine screen for illicit drugs and naltrexone; Franck, J. (2005). weekly of manual-driven tolerability of naltrexone — adverse events (AE) blood samples An open clinical individualised CBT for weeks 4, 8 & 12; adherence — self-report; pil counts; urine screen trial of naltrexone Mean age: not reported relapse prevention for naltrexone metabolites; number of treatment days attended.
Mean years of methamphetamine use: not Mean use in last month: not reported Eleven participants (55%) completed the 12-week study. The fre- tolerability. Nordic quency and amount of amphetamine used were significantly lower Journal of Psychiatry, during treatment compared with pre-treatment consumption, and 59(3): 167–171.
craving scores also decreased among completers. There was a sig- nificantly higher proportion of positive tests of 6-beta-naltrexol in urine among patients completing 12 weeks of treatment compared to those who did not (77% vs 22%); 90% of participants tolerated naltrexone, even when al but two continued to use amphetamines.
Jayaram-Lindström, N. Naltrexone 80 dependent amphetamine users 50 mg naltrexone et al. (2008) Naltrexone daily for 12 weeks and Urine drug screens; Addiction Severity Index (ASI); self-reported double-blind, conducted for the treatment of matching placebo, plus Mean age: 39.4 years amphetamine use (TLFB); Craving Visual Analog Scale (VAS); Appendix: Summary tables amphetamine depend- 60 mins of individual and medication adverse events.
ence: a randomized, Mean years of methamphetamine use: manualised CBT-based placebo- control ed relapse prevention weekly trial. American Journal Mean use in last month: not reported Naltrexone resulted in higher negative urine screens and self- of Psychiatry, 165(11): reported amphetamine use, better retention in treatment and Mean days of amphetamine use in last 12 reduced craving. There was an effect for time in treatment with an increase in mean amphetamine-negative urine screens among both Randomised to naltrexone n=40, placebo n=40 groups over 12 weeks. Treatment was wel tolerated.
Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Coffin, P.O. et al. Aripiprazole 90 dependent methamphetamine 5 mg daily of Aripiprazole Measures
(2013). Aripiprazole (or placebo) for one week, Urine drug screens for methamphetamine; medication adherence double-blind and -reported for the treatment of Males n=79 (87.8%) 10 mg daily for the next (self-report and medication event monitoring system); sexual week, then 20 mg daily risk-taking behaviour; methamphetamine craving; Severity of Mean age: 38.7 years for the remainder of the Dependence Scale (SDS).
retention but fairly randomized, double- Frequency of methamphetamine in past 4 weeks: daily n=19 (21%); Weekly 30-minute CBT controlled trial. 3–6 days week n=43 (47.8%); 2 and MI substance abuse Both groups reduced methamphetamine use, sexual risk taking, Addiction, 108(4): days or less n=28 (31.1%) craving and severity of dependence. Aripiprazole was not superior to placebo in reducing methamphetamine use or any of the other Mean years of methamphetamine United States of use: not reported measures. Aripiprazole participants reported more akathesia, fatigue and drowsiness than placebo. Adherence by MEMS Major depression, history of and self-report was low at 42% and 74% respectively, but not psychiatric medication within the significantly different; 78% of weekly substance use counselling past four weeks and a CD4 cell sessions (839 out of 1080) were completed (aripiprazole 76% count below 200 cells/μl were (408 sessions), placebo 80% (431 sessions); p=0.11).
exclusion criteria.
Randomised to aripiprazole (n=45) or placebo (n=45) Meredith, C. et al. 11 dependent methamphetamine Participants started on A well-conducted 1 mg nightly (one dose Clinical charts, which included demographics, medical and substance open-label low-level study. label pilot study Males n=10 (90.9%) before sleeping) with abuse history, and medications; weekly measures of vital signs Limitations of this of risperidone in dose escalation over four monitored urine drug screen, self-reports of substance use, reports without the treatment of Mean age: 42 years days to 4 mg nightly (or of adverse events and concomitant medication use; Brief Symptom a control small sample size, Mean years of methamphetamine highest tolerated dose).
Inventory (BSI), a neuropsychological testing battery that assessed dependence. Journal use: 8.5 (6.3) years Participants attended a range of functions including speed of information processing of Psychoactive Mean use in last 30 days: 9.9 (7.6) weekly visits with a study learning and memory, executive functioning and abstraction, Drugs, 39(2): psychiatrist and remained language and verbal fluency, and psychomotor function.
on risperidone for four United States of Risperidone was well tolerated and treatment completers showed The dose of risperidone significant reduction in days of methamphetamine use. It is was decreased if Appendix: Summary tables possible that treatment effects may have occurred due to the intolerable side effects increased access and support as a result of participation in the study itself rather than the risperidone. This makes it difficult to draw clear conclusions about the efficacy of risperidone in this population. Participants continued with psychological therapy during the study. Participants completing the study had a final mean daily risperidone dose of 3.6 mg (SD=0.52).
Number and description
Intervention and
comparison if relevant
Primary outcomes including measures used
Meredith, C.W. et 34 dependent methamphetamine Participants entered A well-conducted s for amphetamine-type stimulant u al. (2009). Open users entered the study, 22 received a seven-day open- At screening, all participants received a complete medical trial of injectable injectable risperidone label run-in with oral history, physical examination and routine laboratory tests, and study. There were Males n=19 (86.4%) risperidone. Those who serum prolactin levels. In addition: Structured Clinical Interview; difficulties with tolerated oral risperidone 60-day timeline follow-back interview to quantify self-reported Mean age: 38 years (n=22) were started on methamphetamine and other substance use over the prior 60 Journal of Addiction Mean years of methamphetamine long-acting injectable were higher at the days; a neurocognitive test battery; Addiction Severity Index Medicine, 3(2): risperidone 25 mg (ASI); Brief Symptom Inventory (BSI); Barnes Akathisia Scale; Mean use in last 30 days: 17.1 days intramuscular medication Simpson–Angus Scale; and the Abnormal Involuntary Movement the final N is small.
United States of with subsequent injections Scale were administered to assess movement disorders.
every two weeks to a total Summary
of four injections.
Participants remained on No serious adverse events occurred. Methamphetamine used oral risperidone during was significantly reduced among those who received injections. the first three weeks after Improvements were seen in verbal memory and psychiatric initial injection.
Participants were offered eight weekly individual sessions of relapse prevention counselling.
Aripiprazole, 53 dependent amphetamine users Aripiprazole 15 mg/day A well-conducted Methylphenidate 18 mg/ The primary outcome measure was the proportion of double-blind study with ITT day for the first week, amphetamine-positive urine samples during pharmacological analysis but small Mean age: 32.2 years 36 mg/day for the second treatment.
methylphenidate, Mean years of methamphetamine week, and 54 mg/day high proportion of use: approx. 14 years missing data for Randomised to aripiprazole (n=19), Patients allocated to aripiprazole had significantly more Equivalent gel capsule methylphenidate (n=17) or placebo amphetamine-positive urine samples and those who received American Journal of methylphenidate had significantly fewer amphetamine-positive Psychiatry, 164(1): urine samples than placebo. The trial was ceased after initial analysis reported aripiprazole significantly worsened symptoms.
Appendix: Summary tables Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Topiramate 140 dependent Oral topiramate or placebo was A well-conducted methamphetamine users initiated at 25 mg/day and Primary outcome assessment: urine drug screens three times a double-blind multi-site RCT. Males n=89 (64%).
escalated over the first 35 days of week for % of abstinence.
the treatment of the study up to 200 mg/day or Mean age: 38 years the maximum tolerable dose was Secondary assessments: Clinical Global Impression Scale — Observer (CGI–O) and Self (CGI–S); Brief Substance Craving Mean years of use: not reported achieved. Over weeks 6–12, this Scale (BSCS); Addiction Severity Index (ASI–Lite); Montgomery– Mean use in last month: dose was maintained. Daily dose conclusions based Asberg Depression Rating Scale; drug use self-report; medication could be reduced once during on completers.
controlled trial. maintenance, to the highest adherence by pill count.
Addiction, 107(7): Randomised to topiramate previously tolerated dose. Only (n=69) or placebo (n=71) those tolerating >50 mg/day were Participants who contributed >6 usable urine samples and United States of included. Over the last week of took >50 mg/day of topiramate (or placebo) for 21 days were treatment (week 13), the dose included in the analysis (n=111 (79.3%) were evaluated: 58 was tapered to 100 mg/day for topiramate; 53 placebo). ITT analysis showed similar results to three days, 50 mg/day for two completer-only analysis. Study showed no effect for topiramate days and then 25 mg/day for two in increasing abstinence, but there were significant reductions days. Medication adherence was in reducing use, severity of dependence and improving general measured by pill count.
functioning compared to placebo. Abstinence at entry was related All participants received weekly to abstinence in weeks 6–12. Topiramate recipients experienced brief behavioural compliance significant improvement in observer-rated global severity of enhancement treatment (BBCET), dependence, measured by CGI–O, a non-significant trend toward a manualised, low-intensity decreasing craving over time. Topiramate was safe and well supportive program to promote tolerated. Mean adherence rate was 69.8% for topiramate and medication adherence and 67.4% for placebo. No significant difference between groups in drop-out rate.
Appendix: Summary tables Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
Heinzerling, K.G. Baclofen 10 mg three times per A well-conducted s for amphetamine-type stimulant u methamphetamine users day (tid) for days 1–3 of the Urine samples collected three times a week; ASI–Lite to measure gabapentin Males n=61 (69%) first week followed by 20 mg tid the severity of addiction-related problems in seven areas of until week 16 when the dose was functioning: medical, employment, drug use, alcohol use, legal, variable (Baclofen controlled trial Mean age: 32 years decreased to 10 mg tid for the family/social, and psychiatric; Beck Depression Inventory (BDI); methamphetamine craving measured weekly using a visual methamphetamine use: Or gabapentin 400 mg tid for days analogue scale; pill count for medication adherence.
the treatment of 1–3 of the first week followed by Mean use in last month: 800 mg tid until week 16 when the dose was decreased to 400 mg There were no significant main effects for baclofen or gabapentin Drug and Alcohol in reducing methamphetamine use, craving or retention. For Randomised to baclofen (n=25), tid for the last three days Dependence, baclofen, but not gabapentin, participants who reported taking 85(3): 177–184.
gabapentin (n=26) and placebo Medication was dispensed in a higher percentage of study medication showed significant blister packages. First dose was United States of reductions in use compared to placebo. No differences in taken under supervision of the medication taken or psychosocial sessions attended. Attendance study physician and then were at counselling sessions, lower depression symptoms and less severe dispensed a one-week supply of baseline methamphetamine use were significantly associated with medication in blister packages.
a higher probability of providing a methamphetamine-free urine All participants received a standard sample during the treatment period, but no difference between manual-driven psychosocial groups. The authors concluded that gabapentin does not appear counselling program, consisting to be effective in treating methamphetamine dependence but of thrice-weekly, 90-min. relapse baclofen may have a small treatment effect relative to placebo, prevention group sessions.
but the short half-life of baclofen may limit its use as an anti-craving agent for methamphetamine-dependent individuals.
30 participants: n=27 Vigabatrin was initiated at 500 al. (2005). Safety mg twice daily for three days, Urine samples twice a week; daily vital signs.
briefly reported Vinyl GABA entered and 18 completed the then 1.5 g/day for the next four open-label study, study; 17 participants were also days and 2 g/day for the next week. On day 15, participants At this dose GVG did not produce any visual field defects or altera- the treatment of were placed on 3 g/day, tions in visual acuity or changes in vital signs even with continued control group.
maintained at that dose for the use of methamphetamine and cocaine. The authors concluded that Mean age: not reported next 28 days, and then tapered vigabatrin is safe to use with methamphetamine and cocaine users. were not reported to zero over the next three weeks. Completers reported increased appetite and showed a significant Synapse, 55(2): methamphetamine use: Completers received a cumulative weight gain over non-completers. Based on urine samples taken Appendix: Summary tables dose of 137 g.
under supervision, completers were methamphetamine- and cocaine- United States of Mean daily reported use of All participants were encouraged free for four consecutive weeks (no slips) while two were never drug- nearly 1 g of methamphetamine to participate in weekly group free although use was markedly reduced by self-report. The mean therapy (no indication of how drug-free interval was 40.1 +/– 2.4 consecutive days with an average many did participate).
use of 0.03 +/– 0.02 g/day over the last three weeks of the study. The median onset time to the first day drug-free was 10 days.
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u 60 dependent methamphetamine One week single-blind placebo Preliminary data lead-in followed by seven weeks of Methamphetamine craving; self-reported methamphetamine use; double-blind only reported in Gay bisexual n=21 (50%), HIV+ double-blind fluoxetine 40 mg daily urine screens for methamphetamine.
dependence — a controlled trial: Methamphetamine use declined in both groups. Craving Mean age: 35 years was lower in active treatment group but no other significant differences between the groups on self-reported presented at the methamphetamine use: 7.4 years methamphetamine use or in methamphetamine urine screens for the 30 participants for whom data were available at the time of Mean days per week reporting. No adverse events data reported.
methamphetamine use: 2.6 days Drug Dependence, Mean amount methamphetamine Acapulco, Mexico.
used per week: 2.4 g United States of Randomised to fluoxetine (n=30) daily or placebo (n=30) Mirtazapine 60 dependent methamphetamine Gel capsules containing either users who were sexually active mirtazapine or placebo were Primary outcome was reduction in methamphetamine double-blind and reported administered: 1 capsule (15 mg) metabolite-positive urine test results. Secondary outcomes were Those with major depression or nightly for one week, and then study medication adherence and sexual risk behaviour.
retention rates, antidepressant use in last four 2 capsules (30 mg) nightly for use: a randomized weeks, and HIV-positive men with a CD4 cell count below All participants were offered weekly Mirtazapine group significantly decreased methamphetamine use trial. Archives 200/μL, were excluded.
30-minute substance use CBT and and sexual risk-taking behaviours. Participants assigned to the of General mirtazapine group had significantly fewer methamphetamine- Psychiatry, 68(11): Males n=60 (100%) positive urine test results compared to the placebo group. The Mean age: 40.5 years number needed to achieve a negative weekly urine test result United States of Mean years of use: not reported was 3.1. Adherence was 48.5% by medication event monitoring systems and 74.7% by self-report; adherence was not significantly Mean use in last month: 60% different between arms. Sexual risk behaviours decreased used more than 3 times a week, significantly more among the mirtazapine group (number of male n=10 used (17% daily) partners with whom methamphetamine was used, number of Appendix: Summary tables Randomised to mirtazapine male partners, episodes of anal sex with serodiscordant partners, (n=30) or placebo (n=30) episodes of unprotected anal sex with serodiscordant partners, episodes of insertive anal sex with serodiscordant partners). There were no serious adverse events related to study drug or significant differences in adverse events by arm.
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
229 participants with a Sertraline or placebo at 50 mg/day s for amphetamine-type stimulant u diagnosis of methamphetamine at randomisation. On the eighth Methamphetamine use (urine screen); retention in treatment; craving double-blind well-conducted abuse or dependence (n=227 day following randomisation, dose for methamphetamine (visual analogue scale); depression (BDI); was increased to 50 mg twice and adherence to study medication (pil count, adverse events).
controlled trial daily maintained for the 12-week of sertraline and duration of the trial.
Mean age: 33 years No statistical y significant main or interaction effects for sertraline Contingency management participants observed urine or CM in reducing methamphetamine use were observed using a the treatment of methamphetamine use: 9.3 years samples on Mondays, Wednesdays generalised estimating equation (GEE), although post hoc analyses Mean use in last 30 days: and Fridays. Samples free of showed the sertraline-only condition had significantly poorer methamphetamine metabolites retention than other conditions (χ2(3) = 8.40, p <0.05). Sertraline Drug and Alcohol qualified for a voucher (from conditions produced significantly more adverse events than placebo Dependence, Randomised to sertraline plus US$2.50), which became conditions. A significantly higher proportion of participants in CM 85(1): 12–18.
CM (n=61), sertraline-only conditions achieved three consecutive weeks of methamphetamine (n=59), placebo plus CM (n=54), increasingly valuable (by US$1.25) United States of abstinence than those in non-CM conditions. More participants in or placebo-only (n=55) with US$10 bonus voucher each third metabolite-free urine sample.
the sertraline condition increased methamphetamine use during treatment (n=13) than in the placebo condition. Drop-outs: Plus all participants received sertraline plus CM (30/61), sertraline-only (35/59), placebo plus CM 90-min. Matrix Model relapse (24/54), or placebo-only (22/55).
prevention groups three times per week.
Drop-outs NS between groups, however sertraline-only participants were retained in treatment for significantly less time than participants in al other treatment conditions (χ2(3) = 8.40, p <0.05).
Zorick, T. et al. 229 participants with a Sertraline or placebo at 50 mg/day diagnosis of methamphetamine at randomisation. On the eighth day Increase in methamphetamine use >15% during the last month double-blind Shoptaw (2006). abuse or dependence (n=227 following randomisation, dose was of treatment in the trial, participant-level factors associated with placebo- increased to 50 mg bid maintained this increase.
for the 12-week duration of the trial.
Participants receiving contingency Mean age: 33 years management observed urine samples More participants in the sertraline condition increased on Mondays, Wednesdays and methamphetamine use during treatment (n=13) than in the methamphetamine use: 9.3 years Fridays. Samples that did not contain placebo condition (n=5; p=0.03). The study looked at multiple methamphetamine. Mean use in last 30 days: metabolites of methamphetamine factors from both pre-treatment and in-treatment data that Drug and Alcohol qualified participants for a voucher were associated with increased methamphetamine use during Dependence, treatment. Elevated in-treatment craving for methamphetamine Appendix: Summary tables (from US$2.50) which became Randomised to sertraline plus increasingly valuable (by US$1.25) specifically characterised participants in the sertraline group who CM (n=61), sertraline-only increased their methamphetamine use.
(n=59), placebo plus CM (n=54), with US$10 bonus voucher each 3rd United States of or placebo-only (n=55) metabolite free urine sample.
Plus all participants received 90-min. Matrix Model relapse prevention groups three times a week.
Flumazenil and gabapentin combination
Number and description
Intervention and comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Flumazenil 2 mg infusion on days 1, 2, 3, 22 Measures
methamphetamine users and 23 (or matched saline infusion). On day Percentage of urine samples testing negative for double-blind, well-designed (flumazenil Males n=89 (80%) 1, participants began gabapentin or placebo, methamphetamine during the trial (collected at every clinic placebo- increasing by one capsule (300 mg) per day visit); self-reported drug use; Brief Symptom Craving Scale double-blind RCT. gabapentin) Mean age: 38.5 years to reach the maximum dose of 1200 mg on (BSCS); retention measured by the number of days between RCT Mean use in past 30 days: study day 4. Down-titration began on study the first infusion and the last clinic visit.
but high drop-out approx. 17.5 days day 38 with the final gabapentin or placebo rate, especially dose on day 40. As hydroxyzine is not in the treatment methamphetamine use: considered the key element of the Prometa No effect of the protocol over placebo on measures of group, and large Addiction, 107(2): protocol, all participants received active methamphetamine use, craving or retention in treatment. hydroxyzine in order to reduce the anxiety All participants improved over the trial. There was a three- Randomised to flumazenil/ United States of that might be experienced during the to four-fold reduction in the number of days of self- gabapentin/ hydroxyzine medical procedures, and to assist with sleep. reported methamphetamine use in the past 30 days from (n=60) or placebo (with Participants in both active treatment and baseline. No significant difference between the groups in hydroxyzine) (n=60) placebo groups were administered a 50 mg CBT session attendance: the experimental group attended dose of oral hydroxyzine, with 50 mg take- a mean of 2.95 sessions; and the placebo group attended home hydroxyzine to day 10 prior to each a mean of 2.86 sessions. The investigators concluded that, infusion on days 1, 2, 3, 22 and 23.
in comparison to positive outcomes from another recent All participants received weekly individual trial of the protocol, their null findings may have been CBT-based relapse prevention sessions (up influenced by a strong placebo effect due to considerable publicity about the protocol.
Urschel, H.C. et Medication therapy for four weeks: al. (2007). Open- Flumazenil infusion on days 1, 2, 3, 22 Methamphetamine craving (visual analogue scale); urine open-label study users and had used drug screens; self-report methamphetamine use (TLFB); methamphetamine within adherence to treatment (number infusions, pill count).
treatment program seven days prior to 50 mg oral hydroxyzine prior to infusions targeting type A Gabapentin up to 1500 mg daily Significant reduction in methamphetamine cravings (including thoughts, intensity and frequency), self-reported dysregulation in Mean age: 35.2 ± 7.3 11 weekly individual support sessions methamphetamine use from 70% of 90 days to 42% of 84 days and self-reported use was correlated with urine screen dependence. Mayo results. 90% completed infusions and oral medications. Appendix: Summary tables Clinic Proceedings, methamphetamine use: There were no serious adverse effects.
United States of Mean use in past 90 days: 71.4 ± 19.4 days Number and description
Intervention and comparison if relevant
Primary outcomes including measures used
Active treatment group received flumazenil, Measures
s for amphetamine-type stimulant u et al. (2011). A 2 mg administered intravenously on days Methamphetamine craving (six visual analogue scales and double-blind, and designed controlled trial of users who had used 1, 2, 3, 21 & 22, oral gabapentin up to four categorical scales); self-report methamphetamine use RCT with sizeable methamphetamine within 1200 mg/day and hydroxyzine 50 mg for (TLFB); urine drug screens as indices of methamphetamine previous three days pre-infusion and PRN for sleep (n=68). use and correlates of self-report; adverse events.
drop-out rate not initial treatment of Placebo control group received inactive formulations of the medications (n=67).
mine dependence. Mean age: not reported All participants received Matrix Model Results showed an effect for a combination of flumazenil Journal of Psycho- psychosocial intervention and nutritional and gabapentin in reducing craving in methamphetamine- pharmacology, methamphetamine use: support. To encourage adherence to dependent participants, with the greatest effect 25(2): 254–262.
protocol, participants received incentives demonstrated at day 6 of a 30-day trial. Self-reported United States of Age started drugs: approx. if they completed their appointed visits +1 methamphetamine use was significantly reduced in the day (US$50 voucher for food or gasoline).
treatment group but this was not supported by urine methamphetamine screening in an ITT analysis. Although Mean use in last 30 days: frequency of use was significantly lower in the treatment group than the placebo group at each time point, the Self-reported frequency frequency of use increased in both groups throughout the 30 days before: 89% trial. Seventy-four per cent of the treatment group and 79% treatment; 88% placebo of the placebo group experienced adverse event, most (97%) of which were mild. Close to half in the treatment group (compared to 21% in the placebo group) had injection site reactions. Authors suggest that these medications may offer an option for clinicians seeking to reduce patient craving and increase engagement in psychosocial treatment.
Appendix: Summary tables Medicines not otherwise specified
Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Swanson, A. et al. 20 dependent methamphetamine Varenicline 1 mg twice daily or Briefly reported (2011). Varenicline placebo for eight weeks Urine screens for methamphetamine metabolites; adverse events double-blind (conference for the treatment of No other participant level data Weekly individual counselling of medication.
were reported in this conference using cognitive behaviour pilot study. Paper The varenicline group had higher rates of retention as measured presented at the by days retained in the trial (p=0.009; 21 vs 43 days) and study conducted by this completion (10% vs 60%) with trends toward more mean days research group.
Scientific Meeting of abstinence (3.7 vs 12 days) and greater mean proportion of methamphetamine-negative urine drug screens (9.6% vs 31%). There were no significant differences between treatment groups Drug Dependence, with respect to changes in depression, craving, or in reported Hollywood, Florida.
adverse events. No statistical y significant main effect for varenicline United States of in reducing methamphetamine use was observed. A main effect of smoking status was found in GEE indicating that smokers provided fewer methamphetamine-negative urine drug screens.
Johnson, B.A. et al. Ondansetron 150 dependent Participants were given High-quality and (2008). A prelimi- methamphetamine users ondansetron 0.25 mg, 1 mg, or Weekly proportion of methamphetamine-free urine samples; double-blind, well-conducted nary randomized, 4 mg orally twice daily (bid) or urine methamphetamine level; Substance Use Report (SUR); matched placebo (n=46).
success vs failure at achieving at least three consecutive weeks of placebo- controlled Mean age: 36 years All participants: CBT-based abstinence; ASI–Lite; Hamilton Depression Rating Scale (HAM–D); RCT study of the safety Mean years of methamphetamine relapse prevention 90-min. Brief Substance Craving Scale (BSCS); Clinical Global Impression — group sessions, three times per observer (CGI–O) and self (CGI–S); Methamphetamine Withdrawal Mean use in last month: week from weeks 1–8 Questionnaire (MAWQ) created for the study; study retention.
the treatment of Randomised to ondansetron There were no significant differences in drug use measures, urine national Journal 0.25 mg (n=37), 1 mg (n=29), methamphetamine level, self-reported non-methamphetamine-use of Neuropsycho- or 4 mg (n=38) orally twice daily days, or rates of success vs failure in self-reported achievement pharmacology, and matched placebo (n=46) of at least three consecutive weeks of abstinence. No statistical y 11(1): 1–14.
signifi cant differences among the study groups in the scales of United States of clinical severity of methamphetamine dependence or withdrawal Appendix: Summary tables (MAWQ) or in the rate of change in craving. No differences in retention rates. The average decline in the drug score was signifi-cantly less negative for the ondansetron (0.25 mg b.i.d.) group compared with placebo (p=0.04) but after correction for multi-ple comparisons, it was NS. Ondansetron was wel tolerated, and adverse events were more likely to be reported in the placebo group compared with two of the three ondansetron treatment groups. Number and description
Intervention and comparison
if relevant
Primary outcomes including measures used
Heinzerling, K.G. 88 dependent methamphetamine Baclofen 10 mg three times per A well-conducted s for amphetamine-type stimulant u day (tid) for days 1–3 of the Urine samples collected three times a week; ASI–Lite to measure double-blind, study, but drop- first week followed by 20 mg the severity of addiction-related problems in seven areas of placebo-controlled tid until week 16 when the dose functioning: medical, employment, drug use, alcohol use, legal, controlled variable (baclofen trial of baclofen Mean age: 32 years was decreased to 10 mg tid for family/social, and psychiatric; Beck Depression Inventory (BDI); and gabapentin for the last three days.
methamphetamine craving measured weekly using a visual the treatment of methamphetamine use: 9.5 years Or gabapentin 400 mg tid analogue scale; pill count for medication adherence.
Mean use in last month: approx. for days 1–3 of the first week followed by 800 mg tid until Drug and Alcohol week 16 when the dose was There were no significant main effects for baclofen or gabapentin Dependence, 85(3): Randomised to baclofen (n=25), in reducing methamphetamine use, craving or retention. For gabapentin (n=26) and placebo decreased to 400 mg tid for the baclofen, but not gabapentin, participants who reported taking last three days.
United States of a higher percentage of study medication showed significant Medication was dispensed in reductions in use compared to placebo. No differences in blister packages. First dose medication taken or psychosocial sessions attended. Attendance was taken under supervision at counselling sessions, lower depression symptoms and less severe of the study physician, then baseline methamphetamine use were significantly associated with dispensed a one-week supply of a higher probability of providing a methamphetamine-free urine medication in blister packages.
sample during the treatment period, but no difference between Al participants received a standard groups. The authors concluded that gabapentin does not appear manual-driven psychosocial to be effective in treating methamphetamine dependence while counselling program, consisting baclofen may have a small treatment effect relative to placebo, of thrice-weekly, 90-min. relapse but the short half-life of baclofen may limit its use as an anti-prevention group sessions.
craving agent for methamphetamine-dependent individuals.
Batki, S.L. et al. 77 dependent methamphetamine Parallel outpatient groups were Briefly reported (2001). Amlodipine given amlodipine 5 mg, or Depression (BDI); retention; methamphetamine use in grams; amlodipine 10 mg per day, or Mean age: 35.6 years No difference in retention, methamphetamine use (amount, outpatient trial: methamphetamine use: 8 years dollar value), craving, quality of high, or general functioning. preliminary analysis. Mean use in last 30 days: 1.5 g The authors concluded that amlodipine treatment may be Paper presented at ineffective in the outpatient treatment of methamphetamine the Annual Meeting Appendix: Summary tables Randomly assigned to PLA (n=26), AML 5 mg/day (n=25), Drug Dependence, and AML 10 mg/day (n=26) Scottsdale, Arizona.
United States of America Number and description of
Intervention and
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u 60 amphetamine-dependent Citicoline 500 mg/day Well-designed and Gabrielson, B. (2012). outpatients aged 18–70 years, increasing to 1000 mg/day Mood (Inventory of Depressive Symptomatology: Clinician double-blind conducted study diagnosed with bipolar I, II or NOS, in week 2, 1500 mg/day Version — IDS–C); cognition (Hopkins Auditory Verbal Learning placebo- currently depressed or with major at week 4, and 2000 mg/ Test (HVLT)); and drug use assessed by urine drug screens.
placebo-controlled depression; methamphetamine use day at week 6, compared trial of citicoline for in last four weeks with placebo of identical acceptable limits.
bipolar and unipolar 48 participants included in ITT appearance for 12 weeks Citicoline was associated with an improvement in depressive analysis (12 dropped out after symptoms, and longer study survival than placebo. No initial assignment) differences in cognitive outcomes or drug use were found.
dependence. Journal of Affective Disorders, Citicoline group (n=28) mean age: 41.6 years; 15 female, 13 male United States of Control 20 participants mean age: 34 years; 7 female, 13 male Eight men aged 23–46 years with Dexamphetamine daily — schizophrenia and amphetamine dose calculated by match- Urine drug screens; regular visual observation of injecting sites; case study with small sample ing the estimated dose of unspecified psychiatric assessments were undertaken at least size and variable street amphetamine used, to patients with assuming the usual local treatment. High risk level of 5% purity, usually Summary
started at approximately Dexamphetamine did not exacerbate psychosis among this dependence. Journal of one-half this dose, and group. Four patients had good outcomes for both mental adjusted upwards only health and amphetamine use (three patients abstinent and one 16(4): 373–377.
if considered clinically significantly reduced use), two patients had some improvement appropriate. Starting doses in both symptoms and use, and two patients showed no in the range of 20 mg/day improvement on either domain.
– 80 mg/day Camacho, A. et al. 38-year-old female with Modafinil 200 mg/day (2010). Modafinil for quetiapine, bipolar mixed type and with a further increase No formal measures were used. Descriptive clinical opinion only. case study of with single case. bipolar depression methamphetamine use. Patient up to 600 mg/day over High risk of bias.
self-reported depression, poor a three-month period, Appendix: Summary tables family functioning, craving for stabilised on modafinil Patient reported a reduction in fatigue and depressive symptoms abuse. American 600 mg/day, quetiapine without subsequent induction of manic symptoms. Her family Journal on Addictions, 800 mg at night, and support improved. She was able to live again with her mother 19(2): 190–191.
divalproex 1000 mg/day and help with chores around the house. She described a decrease United States of America in her cravings for methamphetamine and achieved six months of abstinence. Number and description of
Intervention and
comparison if relevant
Primary outcomes including measures used
Misra, L. & Kofoed, L. A 45-year-old Caucasian man Risperidone 1 mg twice s for amphetamine-type stimulant u (1997). Risperidone who had become dependent on No formal measures were used. Descriptive clinical opinion only. case study of with single case. methamphetamine 12 years earlier High risk of bias.
and had increased his use during psychosis. American the past 5 years. There had been Within three days the patient noted reduced hallucinations, Journal of Psychiatry, no psychiatric symptoms until delusions and paranoia. After one week mood, affect, 154(8): 1170.
four months before admission, organisation of thought, delusional beliefs, memory, United States of when he reported the onset of attention, insight and judgment improved. After the dose was increased to 1.5 mg twice daily the auditory hallucinations and delusions ceased. Two weeks into treatment he stopped taking risperidone, and his auditory hallucinations recurred. He also resumed smoking and craved methamphetamine. Upon resumption of risperidone treatment one week later, his hallucinations and craving for methamphetamine promptly ceased. Insomnia, impulsivity, and anhedonia also improved.
Sulaiman, A.H. et al. Aripiprazole 49 dependent methamphetamine Eligible patients were (2012). An open-label users with psychosis, 62% smoking treated with an initial dose MINI; Amphetamine Withdrawal Questionnaire (AWQ); open-label study study of aripiprazole Males n=46 (93.9%) of 5–10 mg aripiprazole Brief Substance Craving Scale (BSCS); Positive and Negative for methamphetamine followed by flexible doses Symptoms Scale (PANSS); Abnormal Involuntary Movements group; of very short induced psychosis. Mean age: 34.2 years (5–15 mg/day) from day 2 Scale (AIMS); Barnes Akathisia Scale (BARS); Simpson Angus duration with only Bulletin of Clinical Mean years of methamphetamine to day 14.
Scale (SAS); Clinical Global Impression Scale (CGI–S); Hospital 14-day follow-up Anxiety Depressions Scale (HADS).
but high retention 22(2): 121–129.
Mean amount spent on methamphetamine use in last 30 days: Ringgit Malaysia 1,386.1 Out of 49 patients enrolled, 41 (83.7%) completed the study. (approximately 40% of mean There was a significant decline in the mean PANSS-total and CGI–S scores over the course of the study. The mean reduction was 27.6±21.4 point from baseline on day 14 for total PANSS score and 2.0±1.2 point for CGI–S. Aripiprazole was generally well tolerated during the study. Adverse events were reported in 10 (20.4%) patients. No statistically significant changes were noted with respect to movement-related adverse events.
Appendix: Summary tables Number and description of
Intervention and
comparison if relevant
Primary outcomes including measures used
Nejtek, V.A. et al. Risperidone 80 dependent cocaine or Participants attended for Good-quality study s for amphetamine-type stimulant u (2008). Do atypical methamphetamine users with weekly visits for 20 weeks. YMRS – 11 items; IDS–C-30 – 30-item depression scale; SCQ- double-blind with high drop- diagnosis of bipolar disorder with Study medications were 10 – measures mood and drug craving; PRD–III – somatic out rate and two effectively treat current manic, hypomanic or randomly assigned to two complaints. Higher scores on the YMRS, IDS–C-30, SCQ-10 and trial group RCT with no co-occurring bipolar groups under blinded PRD–III indicate greater severity of mood, cravings and somatic placebo control.
disorder and stimulant Weekly dosing of randomized, double- Mean age: 35.7 years quetiapine was 50 mg/day blind trial. Journal of Randomised to risperidone (n=46) for the first week, 100 mg/ Of 124 consenting outpatients and 94 participants in the Clinical Psychiatry, or quetiapine (n=48)) day for the second week, intention to treat sample that received one week of study 69(8): 1257–1266.
and up to 600 mg/day by medication, an evaluable sample of 80 patients who attended United States of baseline and at least one follow-up study visit was available. The mean ± SD exit dose for quetiapine was 303.6 ± 151.9 Weekly dosing for mg/day and 3.1 ± 1.2 mg/day for risperidone. Both quetiapine risperidone was 0.5 mg/ (n=42) and risperidone (n=38) significantly improved manic day for the first week, and depressive symptoms and reduced drug cravings (p <.0005) 1 mg/day for the second compared to baseline. Decreased drug cravings were related to week, and up to 6 mg/day less frequent drug use (p=.03). The two medications did not significantly differ in their effects on mood symptoms, drug craving or drug use.
Camacho, A. & Stein, 45-year-old Caucasian woman, 200 mg modafinil Brief letter to the M.B. (2002). Modafinil dependent on amphetamine since twice daily, 40 mg/day Self-reported amphetamine craving, depression and anxiety case study of editor about the for social phobia clinical application of modafinil.
dependence. American Journal of Psychiatry, Self-reported decrease in craving for amphetamine, improvement in depression and anxiety. Reported she no longer spent a lot United States of of time looking for street amphetamine so was able to obtain employment, and she reported not experiencing the same ‘high' with modafinil that she experienced with amphetamine.
Shoptaw, S. et al. Olanzapine A review of one randomised One study of olanzapine (2009). Treatment controlled trial involving 58 compared to haloperidol Results from a single study showed that both the atypical Cochrane review.
haloperidol participants (Leelahanaj et al. antipsychotic olanzapine and the older, typical antipsychotic Appendix: Summary tables psychosis. Cochrane haloperidol administered at therapeutic doses were effective in Database of treating amphetamine-induced psychosis. Participants taking Systematic Reviews, olanzapine had significantly fewer extrapyramidal side-effect 2009(1): CD003026.
symptoms than participants taking haloperidol.
United States of America Number and description of
Intervention and
comparison if relevant
Primary outcomes including measures used
Olanzapine 58 participants with DSM–IV All participants treated as s for amphetamine-type stimulant u et al. (2005). A amphetamine psychosis. All were outpatients and started Brief Psychiatric Rating Scale (BPRS); Clinical Global Impression double-blind high-quality study. smokers of amphetamine with with 5–10 mg/day of Scale (CGI); adverse events; medication safety profile (SAS & BAS). randomised No placebo control.
blind comparison a baseline score on the Brief the study drug. After Psychiatric Rating Scale (BPRS) of each seven-day period, with haloperidol the study drug could Both medications were effective in treating symptoms of in the treatment be adjusted in 5 mg psychosis, with at least 40% improvement in the first week. increments or decrements One-third of the haloperidol patients discontinued treatment psychosis. Journal Mean age: 22.7 years within the allowed dose due to extrapyramidal side effects compared to none of the of the Medical Mean years of amphetamine use: range of 5–20 mg/day olanzapine patients. But olanzapine patients experienced Association of during the four-week more weight gain than haloperidol patients. More olanzapine Thailand, 88(3): 43–52.
Exclusion criteria included patients completed the study than did haloperidol patients. The diagnosis of schizophrenia or olanzapine group (n=27, 93%) were significantly more likely to other psychotic disorder, diagnosis benzodiazepine for severe have completed treatment than the haloperidol group (n=19, of substance abuse or dependence agitation or violent 65.5%, (x2=6.73, df=1, p=0.01)).
in past month.
behaviour was permitted.
Randomised to olanzapine (n=29) Trihexyphenidyl up to or haloperidol (n=29) 4 mg/day for <2 days to treat extrapyramidal side effects was permitted.
Misra, I. et al. (2000). Male aged 50 years with history Patient was given an Low-level single Olanzapine treatment of alcohol, cannabis and cocaine outpatient trial of No formal measures were used. Descriptive clinical opinion only. case study of case report with of methamphetamine dependency. Developed persistent olanzapine (5 mg/day), psychosis. Journal paranoid-hallucinatory state after later increased (to 5 mg of Clinical one year of methamphetamine The authors report that olanzapine on two separate occasions effectively treated both acute and residual psychotic states of a 20(3): 393–394.
United States of Within two weeks, his acute psychotic symptoms were reduced, but he admitted to missing several olanzapine doses and to occasionally using methamphetamine. An increased olanzapine dose and abstinence from methamphetamine subsequently eliminated his psychotic symptoms.
The authors suggest that atypical antipsychotics can Appendix: Summary tables be effective in the treatment of acute and residual methamphetamine-induced psychosis.
Number and description Intervention and
comparison if relevant
Primary outcomes including measures used
s for amphetamine-type stimulant u Akhondzadeh, S. & 28-year-old male 50 mg of topiramate on Hampa, A.D. (2005). patient used MDMA the first day, which was Self-report MDMA consumption. No formal measures were used.
with poorly reported Topiramate prevents ecstasy 2–4 times per week for titrated up to 200 mg/ outcomes, no formal consumption: a case report. 4 years; multiple drug day during the second measures and short Fundamentals of Clinical dependence (opiates and week. He was on this Patient reported using MDMA once during the treatment period follow-up period.
Pharmacology, 19(5): alcohol) and long history dose for three months.
and reported no euphoric effects and stated he felt no desire to of use. No other details use MDMA in future.
Fetter, J.C. (2005). 28-year-old female used Mirtazapine 30 mg Mirtazapine for MDMA- MDMA weekly for one nightly; hydroxyzine Self-reported symptoms of depression, anxiety and sleep.
with poorly reported induced depression. year. Abstinent for six 25 mg as needed for outcomes, no formal American Journal on years, with depression measures and short Addictions, 14(3): 300–301.
and anxiety, which the Patient reported feeling ‘pretty good', panic attacks decreased from follow-up period.
United States of America patient said was linked to 4 to 1 per day, sleep improved and ‘symptom remission continued the start of MDMA use.
for the 12-week follow-up period'. Authors conclude that topiramate 200 mg/day appears to have prevented MDMA-induced euphoria in this single case study, but consumption was self-report only and the patient was followed up for three months only. Other amphetamine-type stimulants
Number and description Intervention and
comparison if relevant
Primary outcomes including measures used
Arnold, K.K. & Yager, J. 37-year-old female, 80 mg/day fluoxetine (2007). A case of unexpected plus using ephedrine for Patient tapered herself off ephedrine over a period of eight weeks. single case of minor clinical and selective remission 20 years to maintain Remained ephedrine-free for the following four months.
of a 20-year history of weight, history of major ephedrine dependence depression, eating The case reports on a patient who was using 1.5 mg ephedrine following treatment with disorder, compulsive daily, which is a very small dose (e.g. the recommended low-dose aripiprazole. [Case shopping, illegal activity dose of pseudoephedrine daily for cold and flu is 120 mg, Appendix: Summary tables Reports Letter]. Journal of equivalent to about 48 mg of ephedrine (see jap.physiology.org/ Clinical Psychiatry, 68(10): content/81/6/2611.full)), so these results are unlikely to have clinical application for dependence.
United States of America
Source: http://www.atoda.org.au/wp-content/uploads/rp29-medication-treatment-options.pdf
Articulo cientifico.comparacion entre analogos de insulina e insulinas humanas.dr elvio bueno
CONTROL GLUCÉMICO EN PACIENTES DIABÉTICOS HOSPITALIZADOS. COMPARACION ENTRE INSULINAS HUMANAS Y ANÁLOGOS DE INSULINA EN ESQUEMAS BASAL-BOLOS 1.-Elvio Bueno 2.-Aldo Ojeda, 3.- Shirley Alsina, 4.-Sandra Samudio, 5.- Lorenzo González, 6.- Aldo Benitez, 7.-Dra. Jazmin Vera, 8.-Mirta Cáceres, 9.-Rocio Argüello, 10.- Fabiola Viveros, 11.- Gladys Castro 12.-Rafael Figueredo, 13.-Fabiola Romero, 14.-
The skinless work group: facing the uncertainty of resting on a void
International Journal of Applied Psychoanalytic StudiesInt. J. Appl. Psychoanal. Studies (2015)Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/aps.1430 The Skinless Work Group: Facingthe Uncertainty of "Restingon a Void" MATÍAS SANFUENTES This paper examines the conflicts and resistances that contemporary organizationsface in the effort of generating new and challenging work opportunities. Assumingthe metaphoric and real character of the ‘body of the organization', differentdilemmas that work groups tackle in the generation of collaborative and productivespaces are described. Based on a socioanalytic consultancy carried out with agroup of Reichian body psychotherapists, the study illustrates the complexities todelineate a common strategy and to overcome the threatening porosity and incon-sistencies of the ‘institutional skin'. The lack of a body support is particularlyparadoxical for a group of psychotherapists that base their therapeutic method onbody techniques, and which crystallizes as an institution the place of rejectionand exclusion that Reich and the concern for the body have historically occupied.Copyright © 2015 John Wiley & Sons, Ltd.