Your generosity makes our life-saving work possible. Although these data facilitate our understanding of the relationship between brain structure, compulsivity, and opioid use in treatment and recovery, they do not speak to these associations during active opioid addiction. Further investigation is needed to characterize these relationships in individuals with active use and to identify how these relationships change during addiction recovery transitions.
The study sample only consisted of men. Therefore, it is not clear if these findings extend to women with opioid use disorder.
Furthermore, groups differed with respect to age and premorbid intelligence, and the influence of these factors on study outcomes was not clear. While the authors noted controlling for these factors in follow-up analyses, their effect on results was not explicitly reported.
Though these data facilitate our understanding of impulsive and compulsive impairments and their neural correlates across the addiction and recovery trajectory, the cross-sectional nature of this study limits interpretation. Given that this was not a longitudinal assessment, findings are subject to the potential influence of other factors that may have differed between groups but were unaccounted for e.
Impulsivity was not emphasized in this study. Different patterns of impulsivity between the heroin group, methadone group, and abstinent group were not reported in detail.
Although a previous publication by the same authors offers some insight, it does not provide a full picture of impulsivity and related brain abnormalities over the course of opioid addiction, treatment, and recovery. A better understanding of these cognitive functions can ultimately lead to strategies for enhancing treatment and recovery. Importantly, engaging in methadone treatment a medication frequently used to treat opioid use disorder might help to alleviate cognitive impairment, particularly compulsivity.
For scientists : Opioid use disorder is accompanied by heighted compulsivity, impulsivity, and associated neurostructural compromise to frontal and striatal regions, which appear more pronounced with protracted duration of opioid misuse and persist during abstinence.
Methadone withdrawal can be a difficult and dangerous process. The risk of experiencing a relapse during this phase is extremely high. And as such, it is vital to seek support and guidance from a healthcare provider or addiction specialists before going off this drug.
Most doctors recommend remaining on low doses of methadone to mitigate withdrawal. Once they adjust to the low doses, they can slowly be tapered off the drug completely. Since methadone is a powerful opioid, it can cause an overdose when taken in high doses.
People who consume too much methadone without a prescription or against medical advice are at a high risk of a methadone overdose. Methadone overdose is a medical emergency. Not recognizing the signs or receiving medical attention can result in fatal consequences. Some of the symptoms of a methadone overdose are:. Make sure to contact your doctor or poison control if you think you have consumed too much methadone. Suppose the symptoms progress, head over to the nearest emergency department without delay.
Evzio naloxone injection or Narcan naloxone nasal spray can be used to reverse methadone overdose. However, make sure to call emergency services right after administering this medication. We found significantly decreased FA, decreased AD and increased RD in Scan 2 in extensive WM regions; overlapping regions were found in the left posterior limb and the retrolenticular part of internal capsule, superior and posterior corona radiata, bilateral external capsule and the right superior longitudinal fasciculus.
In addition, the change of FA in the overlapping regions was positively correlated with the accumulated dosage of methadone use, the RD value in Scan 2 and non-planning impulsiveness NPI measured at follow-up. The results suggest that methadone has damaging effects on WM integrity. The dose-dependent pattern and characteristics of the impairment may suggest new strategies for MMT. Methadone maintenance treatment MMT is regarded as the most effective treatment for opioid addiction.
Long-term MMT benefits heroin addicts by reducing heroin dependence, preventing the spread of HIV and improving the abstinence rates and life status of heroin addicts 2. However, as a long-acting synthetic opioid drug, despite its therapeutic effectiveness, its potential to induce neuronal adaptations in the brain of methadone users remains uncertain. Meanwhile, emerging evidence suggests that long-term methadone use may lead to adverse consequences for brain structure, metabolism and function and the neuropsychological status of heroin addicted patients.
Toxic effects on neuromechanisms due to long-term opioid consumption have been demonstrated, which indicate that opioids may alter brain structure and function by regulating the genesis of neurons, glia and their precursors in the central nervous system, or by disrupting gliogenesis 3. Heroin-induced neurotoxic modifications in humans have been demonstrated, while limited observations of methadone-induced neurotoxic effects have been reported. The majority of the previously reported cases were macroscopic lesions observed by neuroimaging, which were induced by acute or subacute use, or an overdose of methadone.
The primary magnetic resonance imaging MRI characteristics of methadone-induced macroscopic neurotoxic effects have been described as reversible, extensive and symmetric brain hyperintensities in the cerebellum, basal ganglia 4 , deep white matter WM of the cerebral hemispheres 5 , subcortical U-fibers 6 , corona radiate and centrum semiovale 7.
Although methadone-related leukoencephalopathy after acute or subacute methadone use has been observed, the influence of chronic methadone exposure remains poorly understood. Previous research measuring cognitive function has demonstrated several negative effects of long-term MMT. Comparisons of the neuropsychological performance of abstinent heroin addicts and former heroin addicts on MMT have revealed a wide range of impairments in cognitive function in MMT patients, including processing speed, visual-spatial analysis, cognitive flexibility tests, working memory, sustained attention, executive function, verbal and non-verbal learning and resistance to distraction 8 , 9.
However, the underlying neural mechanisms associated with the observed MMT-related cognitive impairments remains uncertain. For instance, one study reported that striatal dopamine transporter uptake was compromised in heroin addicts undergoing MMT compared with that in patients with prolonged abstinence In a previous study, we observed a decrease in WM integrity induced by methadone in the splenium of the corpus callosum and a negative correlation between WM integrity and the accumulated dosage of methadone consumed, by applying diffusion tensor imaging DTI with the regions of interest ROI-wise method However, the limitations of the previous study make it difficult to interpret the methadone-related negative effects.
Specifically, the former study used a group comparison design, in which the effect of previous heroin use could not be eliminated and did not use quantitative methods to measure WM integrity. Therefore, the aim of the present study was to explore whether long-term MMT would induce impairments in WM integrity using a quantitative DTI assessment and a longitudinal self-control design. The correlations between WM alterations and methadone use and neuropsychology scores were determined.
It was hypothesized that WM integrity in MMT patients would decrease after a one year treatment program and the observed impairment of WM integrity would be related to the dosage of methadone and neuropsychological scores. Hence, 33 patients who completed both MRI scans were included in the final analysis. The demographic data, heroin addiction history and MMT status are summarized in Table 1 ; the depressive, anxious and impulsive scores are summarized in Table 2.
All the participants met the initial inclusion criteria of having a stable MMT status; however, all of them were outpatients and reported occasionally using heroin during the interval between the two scans. Therefore, the frequency and accumulated dose of occasional heroin use which were confirmed by interview and monthly urine tests were recorded Table 1. The overlapping regions with decreased FA, decreased AD and increased RD were mainly located in the left posterior limb and retrolenticular part of the internal capsule, the superior and posterior corona radiata, the bilateral external capsule and the right superior longitudinal fasciculus Fig.
Regions with decreased FA and decreased AD were mainly located in the bilateral external and internal capsule, superior longitudinal fasciculus, corticospinal tract, right posterior thalamic radiation, anterior corona radiata and the corpus callosum Fig. Decreased FA and increased RD were located in the bilateral superior corona radiata, external capsule, corticospinal tract, superior longitudinal fasciculus, left posterior limb and the retrolenticular part of internal capsule Fig.
S 1 and S 2 are Scan 1 and Scan 2 , respectively. Regions with decreased FA and decreased AD are shown in yellow b. Regions with decreased FA and increased RD are shown in purple c. There were no significant correlations between the changes in the DTI indices and occasional heroin abuse within one year. There had been no significant correlation between the DTI indices in Scan 1 and any of the initial neuropsychological scores.
The proportion of change in FA in the overlapping regions was positively correlated with the accumulated dosage of methadone use within one year a. To the best of our knowledge, this is the first study to provide direct evidence that chronic methadone consumption has damaging effects on WM integrity, using a longitudinal self-control design and quantitative DTI methodology. The findings are consistent with the hypothesis that chronic use of methadone impairs WM integrity.
Methadone is a highly lipid soluble synthetic opioid and it is well-absorbed in the brain with a strong affinity for u -opioid receptors 12 , which are predominately located in the limbic system and the cerebellum in humans 13 , Although methadone has similar chemical properties and receptor-mediated actions to heroin, relatively specific regional effects of methadone have been reported.
Previously published studies have reported that methadone is distributed mainly in the frontal cortex, hippocampus, cerebellum and the basal ganglia, as detected by immunohistochemistry in patients with a lethal methadone intake 15 , The WM regions with impaired integrity in the present study were mainly those that form connections between the frontal, temporal, parietal and occipital lobes and the limbic system.
The distributions of WM impairment may reveal specific regions where methadone was involved and may help to explain the MMT-induced functional impairment. DTI analysis is capable of measuring WM integrity and FA is an important index that is highly sensitive to WM microstructural changes, but not very specific to the characteristics of these changes Therefore, the overlapping WM regions with decreased FA, decreased AD and increased RD in the present study may provide more detailed pathological characteristics of WM microstructural changes.
It was demonstrated that changes in AD are associated with axon changes, while RD implicates the nature of the myelin In the human central nervous system, myelin is constructed by oligodendrocytes, which express u -opioid receptors In the present study, significantly increased RD values that hinted of specific demyelination were observed in Scan 2 compared to Scan 1 , which validated the harmful-effects of methadone on myelin sheets 20 , The direct effects of methadone on WM integrity remain uncertain, as the changes might have resulted from the demyelination induced by direct impairment or by the activation of an immunological response to neuronal tissues 5.
The results of animal studies indicate that cell death through apoptosis is related to opioid exposure that is induced by mitochondrial dysfunction, oxidative stress, upregulation of the pro-apoptotic proteins Fas, FasL and Bad and a significant loss of mitochondrial membrane potential 23 , 24 , Opioid-induced apoptosis of microglia cells and neurons in humans has also been reported Therefore, apoptosis caused by opioid use including methadone may induce demyelination and axon impairment.
Several reported impairment mechanisms of methadone, such as respiratory depression and systemic hypoxia, have an indirect influence on WM, which can induce chronic hypoperfusion or hypoxia in the brain. According to the animal model of chronic cerebral hypoperfusion, chronic hypoperfusion can significantly reduce the myelin basic protein, which is regarded as a marker of myelin and sequentially reduce the neurofilament H, which is considered to be a marker of axonal proteins Thus, chronic hypoxia may contribute to the pathological characteristics of methadone-related WM impairment, which is currently seen as demyelination accompanied by impairment of the axon.
Impulsiveness has been reported to be associated with substance abuse and related problems, such as relapse 28 , 29 , NPI has been used to measure the subtypes of impulsiveness, which reflect lack of self-control and intolerance of cognitive complexity It has been demonstrated that NPI scores are associated with the severity of craving and indirectly related to the possibility of relapse via craving A positive correlation between RD values in the left posterior limb and the retrolenticular part of internal capsule, superior and posterior corona radiata, bilateral external capsule and the right superior longitudinal fasciculus in Scan 2 and NPI scores measured at the one year follow-up in this study, may reflect a potential relationship between methadone-related demyelination and increased impulsiveness.
However, it is still unclear whether demyelination has a direct effect on the higher heroin relapse rate of MMT patients. Previous studies have observed that methadone exposed infants and children of female heroin users exhibit an altered maturation of WM, which may underlie some of the increased risk for cognitive and behavioral difficulties in these children 33 , Therefore, it is hypothesized that the WM integrity impairment induced by methadone may be related to the pathological basis of the neuropsychological or functional abnormalities in MMT patients.
In the current study, the FA values in the overlapping regions were positively correlated with the accumulated dosage of methadone use within one year, which may suggest a dose-dependent pattern of the methadone-related WM impairment.
Another interesting finding was the relative asymmetry of the FA decrease between the hemispheres; we found that most of the regions with significant FA decreases were located in the right cerebral hemisphere. Previous findings have demonstrated that opioid dependent individuals exhibit a left-greater-than-right asymmetry of cerebral blood flow, which is the opposite of the asymmetry observed in healthy controls However, whether this left-greater-than-right asymmetry of cerebral blood flow in MMT patients has the potential to induce the vulnerability of WM in the right hemisphere requires further investigation.
The findings of the current study have clinical significance. Studies have confirmed that alterations in WM integrity are reversible after certain types of physical or pharmacological treatment 36 , Administering long-chain polyunsaturated fatty acids to infants born to a methadone-maintained mother, which is essential for the formation of myelin, demonstrates a beneficial effect on their problem-solving skills and recognition-memory Therefore, the enhancement of myelin integrity may help to ameliorate the cognitive decline or to decrease the impulsiveness-related relapse in MMT patients.
The current study has several limitations. First, a major limitation is the lack of comparison groups in present study. Third, possible gender-related differences of methadone effects on WM were not examined, since there were only three female MMT patients involved. Previous research has reported the existence of gender-related variations in opioid responses A sexual dimorphism in the oligodendrocytes and the WM of rodents has also been reported Instead of controlling withdrawal and cravings, it treats opioid use disorder by preventing any opioid drug from producing rewarding effects such as euphoria.
Its use for ongoing opioid use disorder treatment has been somewhat limited because of poor adherence and tolerability by patients. National Institutes of Health. Drug Topics. More Drug Topics. Quick Links. About NIDA.
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