Chronic psychoactive substance users are associated with a wide variety of neuropsychological impairments, although there is no consensus on whether the impairment are permanent or temporary1,2. The chronic opioid users are associated with dysfunctional frontal networks3, which lead to impaired executive function and attention4. In addition, Baldacchnio et al. (2012)5 reviewed 52 articles relative to studying on how opioid affects neuropsychological function in adult patients with chronic opioid use/dependence using meta-analysis. Their analyses suggested that chronic opioid exposure is associated with impairment across variety of neuropsychological domains, including cognitive flexibility.

Current treatment for opioid dependence in practice remains controversial, although agonist maintenance using methadone or buprenorphine is the treatment of choice6,7. Methadone-maintenance-therapy (MMT) although has been suggested as effective for opioid dependence in retaining opioid-addicts in the treatment rather than buprenorphine8 and may ameliorate some of its cognitive deficits9,10,11,12,13. However, contradictory results have also been reported, viz., that patients on MMT have more neuropsychological impairments than do currently abstinent former opioid abusers14,15. Bracken et al.16 found that opioid-dependent patients on MMT exhibited poor performance in psychomotor speed, selective attention and impulsivity, which implies a cognitive impairment caused by MMT. In addition, after MMT is discontinued, patients may relapse to opioid use17. MMT alone may not be sufficient for treating opioid dependency.

Memantine (M), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been used for more than 15 years in Europe to treat a variety of neurological diseases. Relatively recently, it has been widely prescribed (usually ≥ 20 mg/day) to treat moderate-to-severe Alzheimer's disease (AD) because of its reported benefits for people with AD18. Memantine, a widely recognized as NMDA antagonist19,20, but its mechanism of action is not fully understood.

Memantine at higher doses (7.5–20 mg/kg; s.c.) attenuates morphine-induced tolerance, physical dependence and drug-seeking effects in animals21,22, its mechanism was believed to be its ability to antagonize NMDA receptors. Moreover, memantine has also benefits on people who display cognitive decline, including brain tumor23, Parkinson's disease24, alcoholism25 and psychiatric disorders26.

Memantine has been suggested to suppress the development, expression and maintenance of opioid dependence and to reduce morphine self-administration in laboratory animals8,21,27. Afterwards, Bisaga et al.28 had a pilot study to demonstrate the effect of memantine attenuating the expression of opioid withdrawal symptoms and lowering the severity of precipitated withdraw in large dosage (60 mg, PO qid) and very small sample (five opioid-addicts with cross-over design). Although, afterwards, Krupitsky et al.29 demonstrated that memantine significantly reduces the withdrawal symptoms in detoxified opiod-dependents and provided a rationale of using the NMDA antagonist memantine to treat opioid addicts. In their study, they used the initial dose of 10 mg/day was gradually increased to the final dose of 30 mg/day over a period of 1 week. Although, significant effective of memantine in previous studies to reduce withdrawal symptoms and severity of opioid dependence, dose-related adverse effects of memantine have been noticed, including dizziness, restlessness, headache, hallucinations, vomiting, hypertonia and a feeling of pressure within the head30. Using such large dose of memantine in the previous study may be considered another issue in the future.

More recently, a relative lower-dose (0.2 mg/kg) of memantine, abolished morphine-induced conditioned-place-preference behavior in rats because of its N-methyl-D-aspartate (NMDA) receptor antagonist was reported31 for the neuroprotective effects. The dose condition could be a very special and highly original finding which is never reported ever for memantine. The extent of memantine dose in treating opioid-addicts remains unspecific and inconsistent, using such large dosage of memantine similar to Bisaga et al. (2001) and Krupitsky et al. (2002) may not only increase side effects but also confuse the detailed mechanism of medication. Using ultra low dosage might be better to demonstrate the specific effect of the memantine in studying its neuroprotective effect.

Since using large dose may increase side effects and might bias the mechanism of therapeutic effect of using memantine. Previously, an addict-animal model using low dose of memantine was reported the ultra-low dose effect, that addictive behavior was changed (Chen et al., unpublished data). Calculating the dosage in the animal to human, the ultra-dose of 5 mg/day memantine was applied in this study. In this study, we proposed to investigate whether a low dose of memantine would attenuate chronic opioid-induced dependent behavior and have beneficial on cognitive improvement. A double-blind, randomly stratified clinical trial with add-on low dose of memantine (5 mg/day, oral) or placebo in opioid-dependent users undergoing MMT for 12 weeks was conducted. We hypothesized that (a) chronic opioid users had worse cognitive performance compared to the health controls; (b) methadone-maintenance-therapy may delay cognitive decline; (c) methadone-maintenance-therapy add-on low-dose of memantine may improve cognitive performance compared to MMT only. To verify the effects and mechanism of memantine, a double-blind, randomly stratified clinical trial was conducted to investigate the effects of low-dose memantine on chronically opioid-dependent patients' cognitive performance and self-reported health condition undergoing MMT.