Acute administration of morphine to healthy volunteers (not on any type of opioids) results in positive signal changes in reward-associated regions, including the amygdala, nucleus accumbens, hippocampus, and orbitofrontal cortex (Becerra et al., 2006). Similarly, acute opioid withdrawal (naloxone-precipitated) in healthy male subjects (21–34 years old) increased neural activity in rewards-prediction and reward-association regions, including the pregenual cingulate, caudate, middle orbital gyrus, orbitofrontal gyrus, and putamen. Whereas, reduced neural activity was seen in the areas involved in the sensorimotor integration, network dysregulation, and body attentional monitoring such as the bilateral precentral and postcentral gyri, posterior insula, left anterior precuneus, and bilateral temporal lobe (Chu et al., 2015). Chronic opioid-dependent patients undergoing abstinence also recorded reductions in the midbrain-thalamic grey matter connectivity (Tolomeo et al., 2016). In a separate study on opiate-dependent patients (18–59 years old; 18 males, 11 females), baseline drug use severity and opioid withdrawal symptoms were positively correlated with the neural response to drug cues in the orbitofrontal cortex, nucleus accumbens, and amygdala. Craving, however, did not mediate such changes (Shi et al., 2021). The neurological and behavioral changes seen in opioid abstinent patients are time-dependent as well. For instance, recently withdrawn opioid-dependent patients showed reduced hedonic response to natural rewards, increased drug-related cues, increased cortisol levels compared to opioid-dependent patients that have been abstinent for 2–3 months. Furthermore, the recently withdrawn patients also had stronger dorsolateral prefrontal cortex responses to drug cues and higher cortisol levels (Bunce et al., 2015), indicating neuroplasticity in reward- and stress-associated brain regions over the abstinence period.

Heroin is greatly implicated with impulsive and poor decision-making due to its deteriorating effects in regions associated with cognitive functions (Kirby and Petry, 2004; Pirastu et al., 2006). Past fMRI findings indicate that heroin-dependent individual (HDI) groups had significant functional changes in the left prefrontal cortex, bilateral orbital frontal cortices, and left anterior cingulate gyrus as compared with control groups, where the HDI groups exhibited a disruption in the white matter structural networks (Zhang et al., 2016). Chronic heroin use is associated with white matter structural connectivity impairment in bilateral frontal lobe sub-gyrus, cingulate gyrus, medial frontal gyrus, posterior thalamic radiation, left temporal lobe sub-gyrus, and right superior frontal gyrus (Li et al., 2011) resulting in different activation patterns in the networks of reward, motivation, memory/learning and control that are heavily involved in drug abuse and addiction (Zhang et al., 2011). Functional connectivity is also compromised in chronic heroin users due to the dysregulation of brain regions (prefrontal cortex, anterior cingulate cortex, supplementary motor area, ventral striatum, insula, amygdala, and hippocampus) that lead to the decrease of the monitoring function, impairing inhibitory control and inducing deficits in stress regulation (Liu et al., 2009). The aforementioned neurological changes weakened the executive control, which manifests as increased impulsivity, based on findings from the Iowa Gambling Task (IGT) and the Barrett Impulsiveness Scale (BIS), where a positive correlation was found between poor performance in the IGT (indicating impaired decision making) with heroin use (Qiu et al., 2011; Ma et al., 2015). As for the BIS, studies investigating impulsivity in heroin-dependent individuals showed that weakened executive control is positively correlated with the BIS score (Qiu et al., 2013; Wang et al., 2016).

Acute fentanyl treatment (50 ug/kg/i.p) to rats decreased [123I]b-CIT binding to dopamine transporter in the striatum by 30%. Similarly, in a human subject, reduced [123I] b-CIT binding was noticed in the basal ganglia by 37% in the presence of fentanyl. Whereas, subacute (10 ug/kg, twice a day, i.p) in animals and following 2 weeks of drug-free period (human) recorded no significant alterations in the dopamine transporter activity. The findings indicate the differential effects of fentanyl on the reuptake of dopamine sensitive to the time frame of administrations as well (Bergström et al., 1998). In a more recent study, in nonhuman primates, intravenous self-administration of fentanyl (1 ug/kg) recorded reduced functional connectivity in the brain regions associated with the effects of opioid agonists such as the striatum, cingulate cortex, and midbrain, indicating a reduced function in motoric, cognition, and sensory-related faculties. Whereas, functional connectivity of nucleus accumbens with other regions were increased, suggesting escalation in the activities of regions associated with reward processing, drawing similarity with other types of opioid that promote addiction (Withey et al., 2022). Furthermore, chronic intake of fentanyl also has caused cognitive detriments such as opioid-related acute amnestic syndrome with MRI findings of a patient revealing restricted diffusion of the hippocampi, and 10% loss of volume in the cornu amnomis, subiculum hippocampal subfields, and dentate regions (Butler et al., 2019).

One of the most frequently methamphetamine-associated changes in the brain is cognitive deterioration, which was shown to affect brain regions such as the prefrontal cortex and anterior cingulate cortex that involved in cognitive control, and prefrontal cortex, anterior cingulate cortex, and striatum in decision making (Sabrini et al., 2019). Chronic methamphetamine intake also caused severe gray matter deficits in the limbic, cingulate, and paralimbic cortex, reduced the hippocampal size, and the neurological findings correlated with cognitive impairment (Thompson et al., 2004). Some researchers reported significant improvement in cognitive function after withdrawal from methamphetamine use over 6 months (Proebstl et al., 2019), especially abstinence as long as 1 year was shown to normalize the cognitive function (Ludicello et al., 2010). Some reported slight improvement just after 1 month of abstinence (not significant) (Simon et al., 2010), whereas some findings indicate that even with an average abstinence period of 46 days, both abstinent and dependent patients still perform worse than the control group in cognitive assessments (Farhadian et al., 2017), suggesting a longer duration of abstinence needed to reverse the chronic methamphetamine-induced cognitive deficits. In line with this, a separate study reported that prolonged abstinence from methamphetamine use improved the grey matter volume of cognition-associated regions (Zhang et al., 2018). Such findings also imply the important roles of these brain regions in the development of methamphetamine dependence (London et al., 2015). Compared to adults, adolescent brains are more vulnerable to methamphetamine-induced alterations, even with a shorter duration of use and smaller doses, particularly affecting the frontostriatal system (Lyoo et al., 2015), which is also been reported in adults (London et al., 2015). Using an animal model, it was reported that withdrawal from chronic psychostimulant use remodels the functional architecture of the brain, causing a shift from cortical (sensory/motor) regions to the more subcortical network (Kimbrough et al., 2021). Another common symptom associated with methamphetamine dependence, that is psychosis was reported due to decreased activity in the left precentral gyrus and the left inferior frontal gyrus, and increased activity in the putamen and pallidum (Vuletic et al., 2018).

The dopaminergic neurotransmitter system innervates brain regions associated with addiction, including the striatum, hippocampus, prefrontal cortex, amygdala, and others (Ogawa and Watabe-Uchida, 2017; Menegas et al., 2018). Variations in the inhibitory and excitatory outputs from D1 and D2 receptors of the dopamine system (Kravitz et al., 2012) somehow produces differential responses to rewards, aversive stimuli, and prediction of rewards and punishment (Ljungberg et al., 1992; Mileykovskiy & Morales 2011). D1 receptors are relatively denser in the striatum, nucleus accumbens, olfactory bulb, amygdala, hippocampus, substantia nigra, hypothalamus, and frontal cortex, while D2 receptor and its subtypes are expressed mainly in the cortex, substantia nigra, and hypothalamus (Mishra, et al., 2018).

Acute intake of opioids by opioid naïve subjects was shown to increase the dopamine release in the striatum in preclinical (Spanagel et al., 1992) and clinical (Spagnolo et al., 2019) studies, mediating the reinforcing effects of the drug. In contrast, prolonged exposure to opioids dampens the striatal dopamine release (Jia et al., 2005; Shi et al., 2008; Yeh et al., 2012) due to drug-induced adaptations in the dopamine neurotransmitter system. Such hypodopaminergic state was associated with reward deficiency syndrome, which behaviorally manifests as insufficiency in the feeling of satisfaction (Blum et al., 2015). Nevertheless, there have been conflicting findings in the dopamine levels of chronic opioid users, consistent with a human postmortem study that reported no difference in striatal dopamine transporters between opioid users and healthy deceased subjects (Kish et al., 2001; Cosgrove, 2010). However, reduced dopamine levels may induce feedback mechanisms to increase dopamine receptor expressions, which has been reported in a postmortem study of opioid users, where both D1 and D2 receptors were upregulated in the ventral tegmental area, nucleus accumbens and the amygdala (Sadat-Shirazi et al., 2018).

Psychostimulants invoke higher dopamine release in the ventral striatum compared to opioids, upon acute intake (Martinez et al., 2003; Spagnolo et al., 2019), which could be due to the direct actions of the stimulants on the dopamine transporters (Tsukada et al., 1999). Studies indicate that there is a general downregulation of dopamine receptors with stimulant use, where the action of methamphetamine is dose-dependent with methamphetamine acting primarily as a dopamine transporter blocker at low concentrations and reversing dopamine transport at high concentrations (Calipari et al., 2013; Ashok et al., 2017). Such changes cause deficits in functions of the dopamine receptors-enriched brain areas, which could be the reason why drug-dependent users crave or even relapse because the endogenous dopamine is no longer sufficient for stimulation (Wang et al., 2012; Härtel -Petri et al., 2017). The reductions in both pre-and postsynaptic dopamine receptors possibly due to the loss of dopamine neurons or damage to the dopaminergic terminals, mediated by methamphetamine-induced apoptosis through activation of caspases and formation of free radicals (De Vito and Wagner, 1989; Tata and Yamamoto, 2007; Cunha-Oliveira et al., 2008). Chronic administration of methamphetamine reduces the levels of dopamine transporters in the striatum, orbitofrontal and dorsolateral prefrontal cortex, and amygdala (McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001; Sekine et al., 2003). Animals that self-administered methamphetamine exhibited dose-dependent decreases in striatal dopamine and striatal dopamine transporter levels, as well as significant reductions in dopamine and dopamine transporter levels in the cortex (Krasnova et al., 2010). Exposure to methamphetamine reduced the levels of dopamine transporter availability which is suggested to be the mechanism behind deficits in inhibitory control that emerge in dependent individuals (Groman et al., 2012). However, there have been studies that reported no effects of methamphetamine treatment in the striatum and nucleus accumbens (Melega et al., 2008).

Opioid receptor subtypes are mu (MORs), kappa (KORs), and delta (DORs) (For review on opioids alone, kindly refer to Darcq and Keiffer, 2018). The MORs mediate behavioral changes such as motivational aspects (Laurent et al., 2015), impulsivity (Olmstead et al., 2009), aversion processing (Boulos, 2016), and despair-like behavior (Lutz et al., 2014). The MORs bind readily to endorphins and are mainly found in the mesocorticolimbic networks (Le Merrer et al., 2009). The KORs bind to dynorphins and act as an “anti-reward” system (Koob and Le Moal, 2008; Koob et al., 2014), mediating negative affective states such as depression, stress, dysphoria, and aversion (Crowley and Kash, 2015), that are more pronounced during the abstinence period of opioid dependence (Chavkin and Koob, 2016). The KORs are present in the striatum, hypothalamus, and periaqueductal gray (Wang, 2019). The MORs potentiates dopamine release in the nucleus accumbens, whereas the KORs inhibit dopamine release terminals in the nucleus accumbens and prefrontal cortex, hence causing dysphoria (Spanagel et al., 1992; Bals-Kubik et al., 1993). The initial positive, and negative reinforcing effects in the later stage of addiction allow the transition from recreational drug use to dependence (Gerrits et al., 2003). In rats, exposure to morphine significantly elevated the levels of accumbal MORs, but decreased levels in the ventral tegmental area (Vassoler et al., 2016). Withdrawal from chronic morphine, however, enhanced the MOR activity in the ventral tegmental area suggesting it may be an adaptive response to the elevation of cAMP levels during morphine withdrawal (Meye et al., 2012). Furthermore, withdrawal from morphine also increased MOR mRNA levels in the other reward-associated regions including the lateral hypothalamus, nucleus accumbens core, and caudate-putamen (Zhou et al., 2006). Nevertheless, the chronic opioid or withdrawal-induced mRNA changes have been inconsistent where some reported a decrease (Duttaroy & Yoburn, 2000), an increase (Sehba et al., 1997) while another reported no changes (Castelli et al., 1997), which could be due to the differences in the brain regions examined, exposure time, dose and route of opioid agonist administration.

Prolonged administration of opioids also decreased endogenous endorphin production, where administration of Fentanyl slowed down the endorphin production in patients under general anesthesia (Ballantyne, 2017). Furthermore, there is also downregulation of MORs along with the uncoupling of MORs from their ligand-gated voltage channels (Sprouse-Blum et al., 2010), causing the users to be dependent on the exogenous opioids to replicate the endogenous opioids that are unresponsive, mediating the risk for drug tolerance and addiction (Toubia and Khalife, 2019). Contrary to MORs and KORs, the DORs are not associated with the drug reward system, but more towards learning and memory (Klenowski et al., 2015; Pellissier et al., 2016), and also attenuates negative mood (Lutz et al., 2014). The DORs bind to enkephalin and are expressed in the basal ganglia (Wang, 2019), mood, motivation, and learning-related regions (Erbs et al., 2015). Chronic intake of morphine decreased the density of DOR-expressing neurons in the mice hippocampus, which persisted even after 4 weeks of abstinence (Erbs et al., 2015). This contributes to reduced inhibition of the firing activity of the hippocampus, resulting in disturbances in memory processes (Erbs et al., 2015), which is commonly reported as cognitive deficits in opioid-dependent patients, especially during the early period of abstinence (Rapeli et al., 2006).

Neuroadaptation occurs with the persistent increase in striatal MOR following methamphetamine treatment, which occurred concurrently with the emergence of anxiety-related symptoms during withdrawal (Georgiou et al., 2016). Opioid receptors do not respond similarly to methamphetamine, where a study using a 7-days regimen revealed that binding of MOR was not changed on day 2 and 5 but downregulated on day 8 then gradually returned to normal on day 11—while there were no changes in KORs and sigma opioid receptors on any given day examined (Chiu et al., 2006). Activation of the dopamine receptor is required for the increased expression of MOR mRNA, at least in the nucleus accumbens (Azaryan et al., 1996), in the presence of stimulants such as cocaine, indicating a substantial interaction between the dopaminergic and opioid system mediating the rewarding effects of stimulants. Moreover, it was also reported that the MOR is important in modulating the development of methamphetamine-induced behavioral sensitization through the dopaminergic neurotransmission (Tien and Ho, 2011). Further corroborating this were findings by Park and colleagues, who reported a decrease in the dopamine 1 receptor-ligand binding in the striatum of methamphetamine-treated MOR knockout mice (Park et al., 2011).

In a tail withdrawal test, methamphetamine (5 mg/kg) was as analgesic as 10 mg/kg morphine. However, the lower doses of methamphetamine (1 and 2 mg/kg) were not. The analgesic effects of methamphetamine were reversed by administration of naltrexone (1 mg/kg; non-selective opioid receptor antagonist), indicating the interaction between MORs and methamphetamine at higher doses. The analgesic effects of 5 mg/kg of methamphetamine were equipotent to the morphine (10 mg/kg) (Ridzwan et al., 2018). It was previously reported that daily intake of methamphetamine (2.5 mg/kg) significantly reduced the expression of MORs (Chiu et al., 2006). The researchers reported a profound decrease in the expression of MORs on day 8, not day 2 or 5, whereas Ridzwan et al. (2018) conducted the tail withdrawal test minutes upon drug administrations. At present, it is unclear whether methamphetamine able to reduce the threshold for analgesic activity by downregulating the MORs within a shorter time frame.

Co-use of methamphetamine and morphine may alter the brain and behavior differently compared to the use of either drug alone. Previous studies have reported greater rewarding effects from the co-use of morphine and methamphetamine compared to the individual doses of the drugs (Negus et al., 1998; Ranaldi and Wise, 2000). A combined administration of methamphetamine (0.75 mg/kg) and morphine (5 mg/kg) produced higher conditioned place preference (CPP) and slower decline of CPP than equivalent individual doses of the drugs (Lan et al., 2009). Such drug-induced reinstatement has also been reported in other preclinical studies testing low doses of morphine (2 mg/kg) and methamphetamine (0.5 mg/kg) (Manzanedo et al., 2005; Tatsuta et al., 2007), which coincides with human findings where low doses of morphine and methamphetamine were reported to mediate the reinforcing effects (Lamb et al., 1991; Melega et al., 2007). Similarly, repeated administration of combined low doses of methamphetamine (0.75 and 2.5 mg/kg/day) and morphine (5 mg/kg/day) for 5 days was reported to elevate dopamine level in the nucleus accumbens compared to either drug alone (Zhu et al., 2015), indicating the higher reinforcing effects of the drugs when taken together.

Challenge administration of morphine (5 mg/kg) and methamphetamine (0.75 mg/kg) on day 40 (post chronic drugs administration) significantly increased striatal dopamine levels compared to either drug alone, but decreased dopamine turnover in the striatum (Lan et al., 2009). Whereas, challenge administration of methamphetamine alone (0.75 mg/kg) significantly decreased dopamine turnover, but morphine (5 mg/kg) produced no profound changes. The reduction in combined drug-induced dopamine turnover was lesser than methamphetamine-induced (Lan et al., 2009), indicating differential effects of the combination of drugs than either drug alone on striatal dopaminergic neurotransmission in the development of behavioral sensitization. Similar findings were also reported in a previous study, however on individual doses of methamphetamine (2 mg/kg) and morphine (10 mg/kg), where methamphetamine significantly increased dopamine release and reduced dopamine turnover in the striatum. Whereas, morphine slightly increased the dopamine levels in the striatum, and had no effects on dopamine turnover. Furthermore, the effects of methamphetamine on dopamine release and turnover were greater in the striatum than nucleus accumbens, whereas for morphine, a significant increase in the release and turnover of dopamine was seen in the nucleus accumbens than striatum (Mori et al., 2016). The findings indicate the differences in the effects of psychostimulants and opioids in the mesolimbic and nigrostriatal dopamine systems.

Effects of low doses of cocaine are enhanced in an additive manner by the addition of low dose heroin, where the drug combination significantly increased the extracellular levels of nucleus accumbens dopamine (Smith et al., 2006). The author suggests that the neurochemical effects are likely through MORs and DORs in the nucleus accumbens. However, a study showed that only the MORs in the nucleus accumbens is involved in the reinforcing effects of combined administration of heroin and cocaine where the author suggested that the DOR had no effect on speedball self-administrations because doses might have been too low and DORs is regionally specific to the shell area of the nucleus accumbens (Cornish et al., 2005). Dopamine receptors such as the D1 and D2 receptors play different roles in the combined administration of heroin and cocaine, particularly D1 receptors enhance the individual self-administration of heroin or cocaine, whereas stimulation of D2 receptors inhibits the reinforcing effects of heroin when administered together (Rowlett et al., 2007).

Methadone doses that are considered low, intermediate, and high are <50, 50–100, and >100 mg/day, respectively whereas the dose for methadone maintenance treatment varies between 30 and 125 mg/day (Robles et al., 2002). Oral intake of methadone for over 3 months improved the quality of life and reduced transmission of blood-borne diseases among opioid-dependent patients (Ali et al., 2018). Despite the efficacy of MMT in harm reduction, there are still other clinical concerns regarding the safety of the therapy. The patients undergoing MMT often have co-morbidities, where they are already on prescription drugs, therefore when added with methadone it might lead to unwanted drug-drug interactions, such as the development of “opioid withdrawal-like symptoms” in the case of efavirenz and zidovudine which are common treatments for HIV patients who are highly prevalent under the MMT program (George et al., 2018). Patients with opioid dependence also tend to have higher rates of mood disorders and other illicit substance abuse, where a combination of these factors may lead to the possibility of central nervous system effects and worsening behavioral symptoms (George et al., 2018). Other potential adverse effects of methadone include nephrotoxicity (Atici et al., 2005; Lentine et al., 2015) and cardiotoxicity (Kumar, 2010).

Buprenorphine is an opioid partial agonist that sustains abstinence, delays the time of resumption to opioid use, and retains patients in treatment (Schottenfeld et al., 2005). Buprenorphine has a long half-life of 24–60 h and typical dosages for maintenance treatment are 8–16 mg/day (Walsh et al., 1994; Kampman and Jarvis, 2015). Due to problems associated with diversion and abuse with buprenorphine treatment, the buprenorphine/naloxone combination tablet was introduced (Vicknasingam et al., 2010). Other combinations of buprenorphine exist as well; however, they were injected illicitly, which instead increased opioid dependence (Yokell et al., 2011).

Methamphetamine use was reported among treatment-seeking OUD patients with a prevalence of 85% in the United States (Ellis et al., 2018), where most of these patients recorded a significantly higher percentage of positive results in the urine morphine test which indicated relapse of opioid use (Liu et al., 2018). In addition, methamphetamine use was also associated with a higher risk of buprenorphine non-retention (Tsui et al., 2020). Whereas, another study found no such associations between methamphetamine use and opioid abstinence in OUD pharmacological management (methadone) (Smyth et al., 2018). The overall impact of methamphetamine use on OUD treatment outcomes are still unclear, but patients have described a balancing effect of the drugs (increases functionality of the drug that is associated with a lower perceived need for medications for OUD) that lead towards non-retention of treatment (Mcneil et al., 2020) (Table 1).

A retrospective study in Rhode Island was the first to investigate the efficacy of MMT in fentanyl abuse, which reported that the majority of patients that underwent 6 months of methadone maintenance achieved abstinence (89%), but the relapse rate was still high (59%) (Stone et al., 2018). Silverstein and colleagues analyzed qualitative data from 63 interviews, to investigate the presence of illicit non-pharmaceutical fentanyl in the current environment and how it has affected practices of non-prescribed use of buprenorphine. The participants consisted of OUD patients on non-prescribed buprenorphine, where they used illicit opioids such as buprenorphine not in seek of euphoria, instead as a form of self-treatment. However, some reported that non-pharmaceutical fentanyl defeated the harm reduction brought by buprenorphine as there were unanticipated experiences of withdrawals (Silverstein et al., 2019). However, the Zurich or Bernese method has been considered a valuable modification to buprenorphine induction for the treatment of fentanyl abuse where it utilizes micro-dosing of buprenorphine. Micro-dosing or micro-induction of buprenorphine is a method of administering buprenorphine in small incremental doses during initiation of treatment that slowly builds buprenorphine at opioid receptors without precipitating withdrawal (Ahmed et al., 2021). Overlapping induction of buprenorphine while being on full mu agonists such as methadone is feasible, where patients experienced very mild opioid withdrawal and craving (Hämmig et al., 2016).

Psychosocial interventions in conjunction with medications for the treatment of opioid addiction are approved as a part of comprehensive treatment for opioid addiction such as contingency management (CM) and cognitive behavioral therapy (CBT), with the majority focusing on methadone treatment (Dugosh et al., 2016). Studies showed that CM participants attended more days of treatment and had longer durations of continued abstinence (Hser et al., 2011; Chen et al., 2013) while CBT participants displayed significant improvements in their positive appraisal at the 6-months assessment and lower emotional discharge at the 12-months assessment compared to control group MMT alone (Kouimtsidis et al., 2012). Other psychosocial interventions include behavioral drug and HIV risk-reduction counseling, motivational interviewing, acceptance and commitment therapy, general supportive counseling, and web-based behavioral interventions (Chawarski et al., 2011; Stotts et al., 2012; Gu et al., 2013; Marsch et al., 2014).

In addition to OUD, MMT is also prescribed to chronic methamphetamine users as treatment (Singh et al., 2020). Comparison between the methadone (a full agonist of the MORs) and buprenorphine (a partial agonist of the MORs) in the reduction of methamphetamine craving revealed more significant craving-attenuating effects of buprenorphine during methamphetamine withdrawal (Ahmadi and Razeghian Jahromi, 2017). In another study, buprenorphine significantly reduced methamphetamine cravings compared to bupropion (weak inhibitor of dopamine and norepinephrine reuptake) for 14 days (Ahmadi et al., 2019). Bupropion also did not significantly increase abstinence duration in methamphetamine-dependent patients compared to placebo (Anderson et al., 2015).

N-acetyl cysteine (NAC) reduces the synaptic release of glutamate (Dean et al., 2012). Preclinical studies and early pilot clinical investigations suggested that NAC may be useful in the treatment of methamphetamine dependence, showing good efficacy in suppressing methamphetamine craving however, there was no report made on methamphetamine use outcomes (Ebrahimi et al., 2015). A combination of NAC and naltrexone was found to be no more superior than a placebo in reducing methamphetamine craving (Grant et al., 2010). Modafinil (dopamine reuptake inhibitor), was not effective in decreasing methamphetamine consumption compared to the placebo (Heinzerling et al., 2010). Whereas, another study reported that those who were compliant in taking the modafinil drug were more likely to reduce drug use (Anderson et al., 2012). Both controlled trials were comparing modafinil daily doses ranging from 200 to 400 mg.

Varenicline at 1 mg (an α4β2 nicotinic receptor partial agonist and α7 nicotinic receptor full agonist) taken twice daily for 9 weeks had no significant effects on end-of-treatment-abstinence and treatment effectiveness score compared to placebo in methamphetamine dependence (Briones et al., 2018). Sustained release of methylphenidate (daily dosing regimen of 18 mg at week 1, 36 mg at week 2, and 54 mg for the remaining weeks) on the other hand was safe and well-tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving, and depressive symptoms (Tiihonen et al., 2012; Miles et al., 2013; Rezaei et al., 2015). Methylphenidate is a dopamine reuptake inhibitor (Karila et al., 2010).

Sixteen weeks of CBT reduced methamphetamine dependence and improved the psychological well-being of patients undergoing methadone therapy. The 30 participants in the treatment group became abstinent at post-test and remained abstinent at the 3-months follow-up (Shakiba et al., 2018). The CBT also reduced craving among methamphetamine abusers living with HIV/AIDS (Jalali et al., 2018). Significant reductions in methamphetamine use and psychiatric symptoms were seen following the psychosocial interventions (Polcin et al., 2014; Rawson et al., 2021). The matrix model, which is a multi-component treatment adopting elements of CBT, MI, family, and group therapy, was found to be more effective in increasing methamphetamine abstinence compared to treatment as usual (CBT only) (Rawson et al., 2021). It is reported that sessions of both MI and CBT significantly increased abstinence as well (Baker et al., 2004, 2005). The treatment combining MI and CBT was found to be effective in improving abstinence where participants reported fewer negative consequences of methamphetamine use at follow-up and intensive matrix program produced a higher abstinence rate compared to CBT alone (Smout et al., 2010) (Table 2).

Naltrexone subcutaneous implants (1,000 mg) for 12 weeks showed higher retention of patients with decreased use of heroin and methamphetamine, providing some of the earliest evidence for effective pharmacological treatment (Tiihonen et al., 2012). Furthermore, a combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment in an 18-days experiment was reported to reduce relapse in the cocaine and morphine co-administration (McCann, 2008; Cordery et al., 2014). Apart from that, based on heroin-dependent polydrug abusers with contingency management and buprenorphine maintenance (2 mg for 5 weeks), it was suggested that for patients who have already achieved polydrug abstinence, contingency management may enhance treatment outcomes. However, participants generally did not produce any significant treatment outcomes which could possibly be due to the population sample where buprenorphine-maintained polydrug abusers continued to use illicit opiates at fairly high levels (Downey et al., 2000). The use of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment was studied in morphine and methamphetamine polydrug dependent mice and results show that the combination successfully attenuated polydrug-reinstatement (Suhaimi, 2017).

Methadone maintenance at a relatively high dose of 30 mg/kg a day in 3 h, attenuated heroin and cocaine-seeking behavior, possibly by reducing the incentive value of drug-related cues (Leri et al., 2004). In a separate study, hypothermia was observed after 360 min of coadministration of methamphetamine and morphine. The cooling was beneficial after 30 min (golden hour) of co-administration. During this early stage, methamphetamine plus morphine-induced significant hyperthermia (Namiki et al., 2005). Another study also proved that the lethal effect induced by co-administration of methamphetamine and morphine was significantly and almost completely diminished by cooling from 30 to 90 min afterward, with normal behaviors such as grooming, sniffing, and rearing returned with the normalization of colonic temperature (Mori et al., 2007). Both studies indicated a “golden hour” of between 30 and 90 min for cooling in the treatment of subacute toxicity and lethality produced by the co-administration (Table 3).