Background
Amphetamine type stimulants, including methamphetamine, present a global public health concern. The second most commonly used illicit drug worldwide, approximately 34 million people aged 15–64 (range 14–56 million) were estimated to be using amphetamine type stimulants in 2010 [
1] with 17 million people (range 14–21 million) estimated to have dependence [
2]. Problems from stimulant use in Australia are largely related to methamphetamine, and include psychosis (often requiring hospital admission), dependence, injecting-related risks, high-risk sexual practices, psychological disturbances, and acute cardiovascular and cerebrovascular events [
3]. The current standard care for methamphetamine dependence comprises psychosocial interventions, which shows modest rates of induction and retention with many effects lost at follow-up [
4,
5].
Agonist-type pharmacotherapies are candidates to improve treatment outcomes for methamphetamine dependence. By mimicking the pharmacodynamic effects of methamphetamine [
6], agonists may ameliorate withdrawal and cravings, attenuate the positive effects of methamphetamine use, enable use reduction or abstinence and/or increase engagement with treatment [
7]. Additional harm reduction may be achieved by replacing illegal drug use with a legal, orally administered and regulated alternative. Agonist-type pharmacotherapies have successfully promoted use reduction and treatment retention in opioid dependence [
8] and smoking abstinence for nicotine dependence [
9]. Emerging evidence suggests that dexamphetamine may be effective in reducing cocaine use among heroin-maintained individuals [
10] and a statistical trend in improving sustained cocaine abstinence has been observed in trials of dexamphetamine, modafanil and bupropion [
11,
12].
Both immediate and extended release forms of dexamphetamine have been trialled as agonist-type pharmacotherapies for methamphetamine dependence [
13‐
16]. The active component dexamphetamine induces neurotransmitter release with a similar pattern to methamphetamine. Randomized controlled trials using 60 to 110 mg of dexamphetamine have shown a statistically significant decrease in amphetamine withdrawal (g ~ 0.57 to 0.62 [
13,
14]) and craving (g ~ 0.59 [
14]) and an increase in treatment retention (g ~ 0.72 [
13,
14]). Although there was a significant decrease in methamphetamine use from baseline, the trials appear insufficiently powered to elicit a difference from placebo.
Methamphetamine dependence research is currently limited by a low number of published, randomized controlled trials with adequate sample size, duration and follow-up [
17]. More targeted therapy should also be considered, with increased stimulant dependence at baseline, longer dosing intervals, higher doses and longer duration of treatment correlating with better clinical outcomes for psychostimulant dependence [
7].
Lisdexamfetamine dimesylate (LDX), a dexamphetamine pro-drug, has been developed for the treatment of attention deficit hyperactivity disorder and binge eating disorder [
18]. Once ingested, LDX undergoes rate-limited hydrolysis by enzymes within red blood cells to release l-lysine and dexamphetamine [
19]. The in vivo and rate limited conversion of LDX provides longer lasting therapeutic action with pre-clinical studies showing a slower onset and longer lasting dopamine release in rat striatum compared to similar agonist formulations, immediate release dexamphetamine and methylphenidate [
20,
21]. Pharmacokinetic studies have shown longer time to peak, lower maximal concentration and longer duration of action compared to immediate release dexamphetamine [
22]. The pro-drug also benefits from a reduced diversion or abuse liability with the kinetics of dexamphetamine remaining consistent between intranasal, intravenous or oral administration [
23,
24]. In clinical studies LDX has displayed a lower subjective drug liking by stimulant users when compared to immediate release dexamphetamine and methylphenidate [
24,
25].
Rationale for study
LDX has the potential to improve treatment outcomes for methamphetamine dependence, however there have been no published trials addressing this question. Doses of 100 to 250 mg LDX may be required to match the 60 to110mg used in trials of dexamphetamine for methamphetamine dependence. These doses are higher than the 70 mg LDX currently approved for attention deficit hyperactivity disorder and binge eating disorder. In order to inform the design of phase 3 trials on the efficacy of LDX as a treatment for methamphetamine dependence, the safety of LDX in this population at the required therapeutic doses needs to be established.
The four most common side effects noted by participants in clinical trials of LDX are decreased appetite (27%), insomnia (27%), dry mouth (26%) diarrhea/nausea (both 7%) in adults with ADHD [
18] and dry mouth (36%), headache (14%), insomnia (14%) and decreased appetite (12%) in adults with binge eating disorder [
26]. LDX is contraindicated in persons with known allergy and with concurrent or use within the previous 14 days of monoamine oxidase inhibitors (MAOIs) [
18]. There are also warnings and precautions for serious cardiovascular reactions, blood pressure and heart increases, psychiatric adverse reactions and peripheral vasculopathy (including Raynaud’s phenomenon). On this basis, known contraindications, pre-existing cardiovascular disease and peripheral vasculopathy will be exclusion criteria for the trial, and measurement tools specific to blood pressure, heart rate, psychiatric symptoms, weight and insomnia will be administered (see Table
1). Other adverse effects will be elicited by non-directive questioning at study visits.
Table 1
Schedule of enrolment, intervention and assessments based on SPIRIT 2013 guidelines [
27]
Informed Consent | ● | | | | | | | | | | |
Eligibility | ● | | | | | | | | | | |
Demographic data | ● | | | | | | | | | | |
Height | ● | | | | | | | | | | |
Medical & Psychiatric History | ● | | | | | | | | | | |
Self-reported drug use | ● | | | | | | | | | | |
Concomitant medications | ● | | | | | | | | | | |
Intervention | | | | | | | | | | | |
Treatment as usual (counselling) offered weekly | | | | | | | | | | | |
Dose of Lisdexamfetamine (mg)-dispensed daily | | 100 | 150 | 200 | 250 | 250 | 200 | 150 | 100 | End | FU |
Baseline Measures | | | | | | | | | | | |
MOCA, AUDIT, WTAR, Wender Utah Scale | | ● | | | | | | | | | |
Primary Outcomes | | | | | | | | | | | |
Brief Psychiatric Scale: psychosis & hostility items | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Vital Signsa (Blood pressure, pulse, temperature) | ● | ● | ●t | ●t | ●t | ●t | ● | ● | ● | ● | ● |
Insomnia Severity Index | | ● | | ● | | ● | | ● | | ● | ● |
Patient Health Questionnaire 15 | | ● | | | | ● | | | | ● | ● |
Patient Health Questionnaire 9 | | ● | | ● | | ● | | ● | | ● | ● |
Generalized Anxiety Disorder 7 | | ● | | ● | | ● | | ● | | ● | ● |
Weight (in kilograms) | ● | ● | | | | ● | | | | ● | ● |
Adverse Events Log | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Electrocardiogram | ● | | | ● | | ● | | | | | |
TSQM-side-effects item | | | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Proportion completing dose escalation phase | | | | | | ● | | | | | |
Secondary Outcomes | | | | | | | | | | | |
Substance Use TLFB-MA (Days Used) | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Urine Drug Screen (positive MA) | ●d | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Substance Use TLFB-MA (Days Used) | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Urine Drug Screenc | ●d | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
TSQM-effectiveness item | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Visual Analogue Scale for MA craving | | ●t | ●t | ●t | ●t | ●t | ● | ● | ● | ● | ● |
Amphetamine Withdrawal Questionnaire | | ●t | ●t | ●t | ●t | ●t | ● | ● | ● | ● | ● |
Severity of Dependence Scale | | ● | | | | | | | | ● | ● |
Adapted Opiate Treatment Index (HIV & crime scales) | | ● | | | | ● | | | | | ● |
TSQM-convenience & global satisfaction items | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
Proportion discontinuing once enrolled | | | ● | ● | ● | ● | ● | ● | ● | ● | |
Price would Pay | | ●b | ●b | ●b | ●b | ●b | | | | | |
Similarity to MA Visual Analogue Scale | | ●b | ●b | ●b | ●b | ●b | | | | | |
Drug Effects Questionnaire 5 | | ●b | ●b | ●b | ●b | ●b | | | | | |
Acute Subjective Response to Substances | | ●b | ●b | ●b | ●b | ●b | | | | | |
Trail-making Test | | ●t | ●t | ●t | ●t | ●t | | | | | ● |
Rey Auditory Verbal Learning Task | | ●t | ●t | ●t | ●t | ●t | | | | | ● |
Digit-span sequencing | | ●t | ●t | ●t | ●t | ●t | | | | | ● |
Flankers Test with no-go | | ● | | ● | | ● | | | | | ● |
Digit Symbol Substitution | | ● | | ● | | ● | | | | | ● |
Rapid Information Processing | | ● | | ● | | ● | | | | | ● |