Modafinil for the treatment of methamphetamine dependence
Introduction
Methamphetamine (meth) is a synthetic stimulant which, along with other amphetamines, was widely prescribed in the US in the 1950s and 1960s for obesity and ‘depression’ (Grinspoon and Hedblom, 1975). The drug's label was revised by the Food and Drug Administration (FDA) in 1975 to that of a Class II controlled substance. Although still approved for Attention Deficit Hyperactivity Disorder (ADHD) in children older than six, and as a short-term adjunct for obesity, the drug is often manufactured illegally in small ‘home’ or large ‘super’ labs, using ephedrine, pseudoephedrine, or P-2-P (phenyl-2-propanone) as a precursor (Drug Enforcement Administration, 2005). In 2009, about 1.2 million Americans age 12 and older had used methamphetamine illicitly at least once in the year prior to being surveyed (Substance Abuse and Mental Health Services Administration, 2010). The United Nations estimated that there were about 14–53 million annual users globally, among persons aged 15–64 years (UNODC, 2010).
Dependence on methamphetamine can be a devastating illness, with ill effects and associations across the lifespan, at home and in the community. Neonates who were prenatally exposed to meth had a higher incidence of being small for gestational age, after adjusting for alcohol and tobacco exposure and other covariates (Nguyen et al., 2010). A sample of 526 meth dependent adults, who took part in the Methamphetamine Treatment Project of SAMHSA's Center for Substance Abuse Treatment, were reassessed three years later. Almost half of them (48%) met DSM-IV criteria for a current or past psychiatric disorder other than substance use, and 29% had antisocial personality disorder (Glasner-Edwards et al., 2010). Three of the major illicit drugs associated with criminality were assessed over a 10 year follow-up. The courses of almost 1800 heroin, cocaine, and methamphetamine users showed that meth users had earlier initiation of drug use than cocaine users (age 19.6 vs. 23.0 yrs), and spent more months incarcerated than cocaine users (10.5 vs. 6.3), though less than heroin users (34.7). Meth users were also more likely to be women than were heroin or cocaine users (46% vs. 11% or 29%), and had a relatively high percentage of drug injection (44% vs. 90% or 27%; Hser et al., 2008).
In contrast to methamphetamine, modafinil is a novel, non-amphetamine psychostimulant, first approved by the US Food and Drug Administration (FDA) in 1998 for the treatment of narcolepsy, and later for shift work sleep disorder, and as an adjunct for obstructive sleep apnea (Cephalon Inc., 2007). It is an effective wake-promoting agent, but its mechanism of action differs in some ways from that of the amphetamines, cocaine, or methylphenidate (Ballon and Feifel, 2006). Modafinil has distinctive actions on the hypocretin/orexin system (Scammell et al., 2000) and the glutamate/GABA (gamma-Aminobutyric Acid) systems (Ferraro et al., 1999), as well as some dopamine-mediated (Wisor et al., 2001) and alpha-adrenergic effects (Stone et al., 2002) that resemble those of more traditional stimulants.
There are several rationales for using modafinil to treat methamphetamine dependence. For example, modafinil has stimulant properties, which could be therapeutic for alleviating some stimulant withdrawal symptoms (McGregor et al., 2008). In animal testing it has been found to attenuate reinstatement of meth self-administration (Reichel and See, 2010). Also, modafinil appears to have lower abuse potential than methylphenidate or amphetamine (Jasinski, 2000, Myrick et al., 2004). Modafinil improves cognition and mood (Turner et al., 2004, Taneja et al., 2007), and has shown efficacy in the treatment of child and adult ADHD (Lindsay et al., 2006). Modafinil has been used in several trials of treatment for cocaine dependence, with mixed results (Dackis et al., 2005, Anderson et al., 2009). Finally, modafinil was safe and well tolerated in a Phase I interaction study with intravenous methamphetamine (unpublished data, Jones, 2007).
Section snippets
Methods
The objectives of this study were to evaluate the efficacy and safety of modafinil relative to placebo, for reducing methamphetamine use in meth-dependent outpatients, as assessed by qualitative or quantitative urine drug screens. The study had a double-blind, placebo-controlled, parallel-group design in which, after a 3-week screening/baseline period, participants were randomly assigned with equal probability to one of three treatment groups to receive 400 mg modafinil, 200 mg modafinil, or
Baseline demographics
Fig. 1 shows flow diagram of the numbers of study participants, from consent through randomization and on to completion of the study. The screen failure rate was 51% (226/440). The most common reasons for failure in screening were: (1) not willing and able to comply with study procedures, including ‘did not return to clinic’ (54%); (2) did not provide a methamphetamine-positive urine during the 3-week screening period (19%); (3) had current dependence on a psychoactive substance other than
Discussion
In this study, the effect of modafinil on the planned primary outcome (methamphetamine non-use weeks) was not significant. Also, the ‘terminal abstinence’ outcome, which is recently preferred by the FDA and Cochrane reviews, did not show a medication effect. In addition, other secondary outcome measures did not show significant effects of modafinil to decrease the amount of meth used or increase the length of abstinence (prevent relapse). However, the measurement of study drug in the urine,
Role of funding source
Funding for this study was provided by NIDA Contract # Y1-DA-4006-01. The National Institute on Drug Abuse-NIH had a major role in study design, in the analysis and interpretation of data, and in the writing and submission of this manuscript for publication.
Contributors
Authors Ann Anderson and Ahmed Elkashef wrote the first draft of the manuscript, and Ann Anderson edited the final draft. Shou-Hua Li, Kousick Biswas, Frances McSherry and Tyson Holmes did the statistical design, analyses, reports and editing. Erin Iturriaga contributed literature searches and descriptions of the study population and treatments. Roberta Kahn summarized the adverse events data. Nora Chiang provided chemical assay materials. Elmer Yu and Ahmed Elkashef contributed summaries of
Conflict of interest
All authors declare that they have no conflicts of interest, i.e., no actual or potential conflict of interest including any financial, personal or other relationships with people or organizations within three years of beginning the work submitted that could inappropriately influence, or be perceived to influence, this work.
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2021, Drug and Alcohol DependenceCitation Excerpt :For example, among both cocaine- and methamphetamine-dependent individuals, relapse is associated with less differentiation in the activity of the anterior insula region of the brain during safe versus risky decisions (Gowin et al., 2019). Moreover, there is considerable overlap among candidate medications for treatment of cocaine and methamphetamine use disorders (Anderson et al., 2012, 2009). Despite many similarities, these disorders appear to have somewhat different sociodemographic, neuropsychological, and clinical correlates (Hall et al., 2018).