Introduction

Dependence on drugs and alcohol is a serious worldwide problem from social, economic, and health perspectives (Pakri Mohamed et al., 2018; Das and Horton, 2019; Sontate et al., 2021). Globally, the number of methamphetamine and opiate users has continued to grow at an alarming rate despite numerous stringent drug abuse laws (Bach et al., 2020; Dezman et al., 2020). A recent report indicates a nearly four-fold increase in methamphetamine-related hospitalizations and a more than 10-fold increase in stimulant-related deaths (Winkelman et al., 2018; Ruhm, 2019) surpassing the overdose death rate of prescription opioids (Hedegaard et al., 2020). Likewise, the prevalence of opioid overdose and overdose-related deaths were also escalated in the past years (Stevens et al., 2017; Sivaraman et al., 2021). What’s more concerning is, almost half of psychostimulant use-related deaths involve opioids, and an increase in trend is also observed in opioid use related-deaths involving methamphetamine (Ihongbe and Masho, 2016; Lancet, 2018; Gladden et al., 2019; Kariisa et al., 2019), indicating a spike in polysubstance use (Palamar et al., 2018; Zuckermann et al., 2019; Compton et al., 2021). It is estimated that the global cost for the treatment of 4.5 million drug users is about $35 billion annually (INCB, 2013), which is accounted for only one in six drug users. If all of the dependent drug users were to seek treatment, it would cost an estimated 0.3–0.4% of the global gross domestic product ($200 billion) (INCB, 2013). The cost of untreated and continuing use is significantly higher than investment in treatment alone, research finds. Reports from the United States National Drug Intelligence Center (NDIC) indicate the drug-related healthcare cost includes both direct and indirect costs related to inpatient drug treatment, medical intervention such as emergency services, and research for prevention and treatment (NDIC, 2011).

Currently, one of the most well-researched treatment options for substance dependence is opioid dependence. Methadone maintenance therapy (MMT) has been employed as one of the harm reduction approaches to manage opiate addiction (Ali et al., 2018), with some reporting its efficacy in reducing high-risk behaviors (Zhang et al., 2019), and whereas some have argued that for long term treatment, MMT may not significantly improve the quality of life among patients (Teoh Bing Fei et al., 2016). MMT also requires lifelong commitments from drug users. Other drugs such as buprenorphine or buprenorphine-naloxone are mainly used in private settings due to the high cost, as a maintenance therapy (Vijay et al., 2015). Buprenorphine is an opioid agonist like methadone, whereas naloxone is a short-acting opioid antagonist commonly given by injection to reverse opioid overdoses (Webster et al., 2016). In several countries, buprenorphine or buprenorphine-naloxone combinations were injected illicitly by the majority of opioid users, increasing the incidences of opioid dependence (Yokell et al., 2011). Oral treatment of naltrexone for opioid dependence is ineffective due to poor treatment adherence (Minozzi et al., 2011). Naltrexone implant, on the other hand, has produced some positive results in the treatment of opioid or polydrug abuse (Kelty et al., 2019; Krupitsky et al., 2019). Nevertheless, the clinical efficacy of the implant in the long-term has not been reported and the potential opioid overdose associated with naltrexone implant has not been sufficiently explored (Saucier et al., 2018).

To date, there are no significantly convincing treatment outcomes in the pharmacotherapy of methamphetamine use disorder (MUD) (Morley KC. et al., 2017; Ballester et al., 2017). Systematic analysis of existing literature revealed some positive outcomes with dexamphetamine, methylphenidate, naltrexone, and topiramate, whereas anti-depressants, such as selective serotonin reuptake inhibitors, and tricyclic antidepressants were being the least effective in the management of MUD (Siefried et al., 2020). Individual clinical studies have reported efficacy in the use of buprenorphine (Ahmadi and Razeghian Jahromi, 2017; Ahmadi et al., 2019), N-acetylcysteine (Salehi, 2015), and methylphenidate (Rezaei et al., 2015) in reducing the craving score of methamphetamines, whereas some have reported lack of efficacy among drugs such as bupropion (Anderson et al., 2015), modafinil (Heinzerling et al., 2010; Anderson et al., 2012), varenicline (Briones et al., 2018) in methamphetamine dependence treatment.

Therefore, this present review discusses the human and animal behavioral and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This review also delineates the recent advances in the pharmacotherapy of mono and poly drug-use of opioids and methamphetamine at clinical and preclinical stages.

Opioid Use Disorder

Opioid abuse originates from over prescription for the patients’ pain relief, while the increasing availability of low-cost opioids also has exacerbated its potential for abuse (Darcq and Keiffer, 2018). Patients develop tolerance to the opioid’s analgesic effect after treatment over an extended period. Administration of opioids at a higher dose is used to overcome this tolerance, however, patients will then be vulnerable to severe side effects such as withdrawal symptoms, and the threat of respiratory depression (Hayhurst and Durieux, 2016). Worldwide, the prevalence of opioid use was the highest in North America (UN World Drug Report, 2021). Analysis of individual data from the United Kingdom, United States, Australia, Germany, and France revealed that almost 1 in 5 reported abuse and 1 in 4 individuals reported misuse of opioid analgesics obtained through a prescription (Morley KI. et al., 2017). Heroin, fentanyl and morphine were the most commonly used opioids amongst others which include methadone, buprenorphine, codeine, tramadol, oxycodone, and hydrocodone (UN World Drug Report, 2019). According to WHO estimates, there were approximately 115,000 casualties from opioid overdoses globally, and COVID-19 has further exacerbated the fatality rate (Centers for Disease Control and Prevention, 2020; UN World Drug Report, 2021).

Morphine abuse negatively affects the users once the addiction cycle is engaged due to the tolerance developed following prolonged use of morphine, which is defined as the need to increase the dose to achieve the same initial effect due to decreased analgesic efficacy (Dai et al., 2018). The Food and Drug Administration (FDA) defines a person is opioid-tolerant if the person has been receiving oral morphine 60 mg/day for 1 week, where different types of opioids have different durations such as transdermal fentanyl, oral oxycodone, oral hydromorphone, oral oxymorphone with 25 mg/h, 30 mg/day, 8 mg/day, 25 mg/day, respectively (Rabin et al., 2017). The users potentially succumb to dependence due to the severity of the withdrawal symptoms including abdominal pain, nausea, diarrhea, lacrimation, and generalized piloerection. In contrast to the drug pain-relieving effects, drug cessation in the morphine-dependent state results in the genesis of negative effects such as anxiety, agitation, and dysphoria (Verster et al., 2021). Psychological dependence on the other hand refers to the state of the patient where they are craving for the drug, to relieve its withdrawal symptoms, or for its gratifying effects (Jacobs, 1986). The withdrawal symptoms that are brought forth from abstinence lead to craving with disinhibition, leaving the user vulnerable to relapse (Kalant, 2010; Campbell et al., 2013). Moreover, there was heightened impulsivity and impaired strategic planning in opioid-dependent patients (Tolomeo et al., 2016), along with increased anhedonia (Kras et al., 2018; Kiluk et al., 2019). Withdrawal symptoms are a key driver behind continued abuse, and a barrier to opioid discontinuation (Pergolizzi et al., 2020).

Behavior parameters established using various models of abuse under controlled environmental and drug administration regimens mimic the psychological status of humans in the presence or absence of substances depending on the animal models (Kumar et al., 2013; Kumar et al., 2016; Iman et al., 2021). Likewise, in opioid dependence animal models, depressive-like behaviors are significant at 1 week after prolonged withdrawal where experiments showed that there was a decreasing level of social interaction and elevation in immobility time which reflects a state of lowered mood or depression-like behavior (Anraku et al., 2001). The social avoidance symptoms and emotional despair mirrored by these mice reflect depression (Jia et al., 2013). Anxiety is another prominent affective symptom that manifests during abstinence from chronic morphine administration. Animal studies have shown that there is a significant increase in anxiety-like behaviors in the elevated plus maze and light/dark box paradigms (Zhang et al., 2008; Buckman et al., 2009; Miladi-Gorji et al., 2012). Apart from that, another prominent withdrawal symptom that accompanies abstinence is impulsive behavior, which encapsulate poor inhibitory response control (impulsive action) and impulsive decision making (impulsive choice) where observations suggest that the opioid system plays a significant role in decision making (Pattij et al., 2009). Morphine exposure also increases motor impulsivity in animal models (Kieres et al., 2004; Colin et al., 2012; Moazen et al., 2018), as well as deficits in learning and memory (Iman et al., 2021).

In Europe, fentanyl abuse was related to over 250 fatalities, while in 2017 alone there have been 25 fatalities associated with fentanyl and its synthetics analogs such as carfentanil, butyryl fentanyl, fluorobutyrylfentanyl, furanylfentanyl, and alfentanil (European Monitoring Centre for Drug and Drug Addiction, 2018; Hikin et al., 2018). According to the National Survey on Drug Use and Health in the United States, fentanyl use appears to be on the rise although the most commonly misused prescription opioids are hydrocodone, oxycodone, codeine, and tramadol (UN World Drug Report, 2018). Fentanyl and fentanyl analogs are full agonists at the MOR with varying degrees of potencies, where acetylfentanyl is 5–15 times more potent than heroin (Yonemitsu et al., 2016), butyfentanyl is 7 times more potent than morphine (Steuer et al., 2017) and ocfentanil is almost 90 times more potent than morphine (Fletcher et al., 1991). There is a high demand for opioids that are popularly derived from fentanyl, which are available at a cheaper cost compared to heroin (Marchei et al., 2018; Rothberg and Stith, 2018). Fentanyl is 50 times more potent than heroin (Rothberg and Stith, 2018), it is often found in heroin samples as a cutting agent that is meant to give heroin a much higher potency, which is more favorable to drug abusers (Marchei et al., 2018). Fentanyl also causes drowsiness, sedation, euphoria (lesser than heroin and morphine), respiratory depression, anxiety, hallucinations and have associated with withdrawal symptoms such as diarrhea, abdominal cramps, anxiety, sweating, bone pain, and shivers (Stanley, 2014; Suzuki and El-Haddad, 2017; Kuczynska et al., 2018).

Rats that undergo short-term withdrawal from fentanyl self-administration (0.0032 mg/kg/infusion followed by 24 h abstinence) were found to have a disrupted brain immune response where there was an increase of inflammatory responses in the NAc simultaneously resulting in immunosuppression in the hippocampus (Ezeomah et al., 2020). It was suggested that the changes in immune outcomes in the central nervous system contribute to the relapse in OUD, however, the authors interestingly noted that the inflammation levels did not correlate with the opioid receptor expression (Grace et al., 2015; Liang et al., 2016). Cisneros and colleagues proposed that the fentanyl-associated change in the immune response contributes to neuroimmune adaptations that might drive the development of OUD, and increase the onset and severity of neurocognitive disorders (Cisneros and Cunningham, 2021). Chronic self-administration of fentanyl in rats (2.57 μg/kg per i.v. infusion, 30 days), significantly decreased ultrasonic vocalization, suggesting an aversive response to repeated fentanyl use, thus indicating negative reinforcement (Dao et al., 2021). Cessation of fentanyl administration (1.2 mg/kg/day for 14 days) also resulted in a time-dependent elevation in brain reward thresholds and somatic withdrawal signs, displaying severe deficits in brain reward function (Brujinzeel et al., 2006). In addition, chronic administration of high dose fentanyl (0.3 mg/kg/i.p. for 28 days) reduced anxiety-like behavior in rats in the open field and elevated plus maze tests (Colasanti et al., 2011; Fujii et al., 2019), reduced muscle strength and locomotion (Fujii et al., 2019) On the contrary, during withdrawal, increase in anxiety-like behavior and hyperalgesia was noticed in mice, and neither high nor low doses of fentanyl had any negative effects on the animals’ cognition (Fujii et al., 2019). In a separate study, 25 μg/kg of fentanyl reduced the grimace scale in mice and rats inflicted with injury of the infraorbital nerve (Akintola et al., 2017). In a more recent study, extended access to self-administration of a vaporized fentanyl to rats altered their behavioral economic metrics consistent with the development of an addiction-like state (McConnell et al., 2021).

The Centre for Disease Control and Prevention reported that there were a cumulative 14000 heroin users died from an overdose in the United States (Centers for Disease Control and Prevention, 2020). In addition, there is a 97.5% increase in heroin use among non-medical users of other prescription drugs suggesting increased polydrug abuse (Jones et al., 2015). Key factors behind the polydrug use of heroin and other substances are the high cost and low availability of heroin, making drug abusers seek cheaper and more lasting highs (Siegal et al., 2003; Lankenau et al., 2012; Mateu-Gelabert et al., 2015). Symptoms of heroin withdrawal include restlessness, insomnia, diarrhea, muscle and bone pain and cold flashes, depression, and nausea, peaking around 48–72 h after the last dose and may last 5–10 days (National Highway Traffic Safety Administration, 2004). Chronic administration of heroin (5 mg/kg at 12 h intervals for 34 days) impaired spatial learning and memory along with increased expression of proapoptotic proteins, relating the cognitive detriment to neural apoptotic damage (Garcia-Fuster et al., 2003; Astals et al., 2008). Withdrawal from intravenous self-administration of heroin (5 daily sessions, limited to 25 number of infusions 0.04 mg/infusion after 7 days increased to 75 number of infusions maximum), results in motivational deficit shown by a significant increase in latency to collect earned food, which was hypothesized as a consequence of the diminished perceived value of the food reward (Goldberg and Schuster, 1967; Harris and Aston-Jones, 2003; Dalley et al., 2005).

Methamphetamine Use Disorder

Methamphetamine is a powerful psychostimulant that has been abused as a recreational drug instead of its intended use as a second-line treatment for attention deficit hyperactivity and obesity (Kish et al., 2001). Methamphetamine remains a significant public health concern over its abuse, especially in its crystalline form, where its use is rapidly increasing in East and South-East Asia (UN World Drug Report 2021). According to the UN World Drug Report 2021, the highest prevalence of Amphetamine Type Stimulant (ATS) abuse was reported in North America and the lowest in Africa. But the prevalence of non-medical use of pharmaceutical stimulants and methamphetamine was the highest in North America as well as South East Asia. Malaysia, however, reported 65.2% ATS use among its drug and substance abusers according to the National Anti-Drug Agency Report (National Anti-Drug Agency, 2019).

Clinical findings have associated chronic use of methamphetamine with manifestations of withdrawal symptoms including fatigue, sleep disturbance, dysphoria, agitation or psychomotor retardation, increased appetite, depression, and anxiety (American Psychiatric Association, 2013; Zhao et al., 2021). Anxiety and depression appear to be prominent and severe especially during the early withdrawal period (Zhang et al., 2015; Ren et al., 2017; Luan et al., 2018; Luan et al., 2018), where longer duration of methamphetamine use was associated with a higher odds ratio of depression, and co-occurring anxiety and psychotic symptoms (Ma et al., 2018). Whereas, symptoms such as craving and sleep disturbance were reported to persist as long as 4 weeks of post-abstinence (Zorick et al., 2010; Mancino and Gentry, 2011). Increased impulsivity also was reported among methamphetamine users during abstinence which is suggested to be a negative reinforcer to maintain drug use (Jones et al., 2016). In a study using the Iowa gambling task, methamphetamine dependence significantly affected inhibitory control and decision making, suggesting abnormal reward processing and inhibitory control (Fitzpatrick et al., 2020). Methamphetamine dependence also affects the cognitive ability of dependent users such as visual memory (Moon et al., 2007), attention/processing speed learning/memory, working memory, timed and executive function (Kalechstein et al., 2003), and decision making (Mizoguchi and Yamada, 2019). Moreover, it was also reported that a month of abstinence did not improve the impaired cognition of methamphetamine-dependent subjects (Simon et al., 2010).

Studies employing mice, induced methamphetamine withdrawal through various dosage regimens, where some researchers achieved this by administering the substance through varied durations such as 8 weeks (5 mg/kg, i.p, once a day, 5 days per week; Ru et al., 2019), 2 weeks (2 mg/kg, 12-h intervals; Hosseini et al., 2021), and 10 days (5 mg/kg, i.p, once a day; Georgiou et al., 2016; Jacobskind et al., 2019). Whereas, some tested escalating dose regimen for 10 days (D1: 2 mg/kg, D2: 4 mg/kg, D3-10: 6 mg/kg). Researchers using rats opted for 10 days of methamphetamine exposure (2 mg/kg, intramuscular; Li et al., 2021), some for 14 days (2 mg/kg, 12 h interval; Damghani et al., 2016), 21 days (10 mg/kg; Yasuj et al., 2019), 14 days (inhalation of methamphetamine, 1W: 5 mg/kg, 2W: 10 mg/kg; Rezaeian et al., 2020), 7 days (2 mg/kg once per day, i.p; Etaee et al., 2019), and 4 days (2.5, 5 or 7.5 mg/kg every 3 h, 3 times per day, i.p; García-Cabrerizo and García-Fuster, 2019). Withdrawal from chronic methamphetamine (various doses of methamphetamine given for 8 weeks, 21, 14, and 4 days) resulted in changes in behaviors such as anxiety and depressive symptoms when tested in the open field, sucrose preference test, forced swim test, and splash test (Damghani et al., 2016; Shabani et al., 2018; Ru et al., 2019; Yasuj et al., 2019; Rezaeian et al., 2020; Hosseini et al., 2021). In addition to this, some reported no changes in the locomotion of animals during the withdrawal period (Hosseini et al., 2021; mice; 2 mg/kg, 12-h intervals), whereas some reported increase in locomotion in methamphetamine treated animals (Rezaeian et al., 2020; rats; inhalation of methamphetamine, 1W: 5 mg/kg, 2W: 10 mg/kg). These discrepancies could be due to the differences in strains of animals tested, mode of methamphetamine intake, dose, and duration of intake as well.

Co-Abuse of Opioid and Methamphetamine

Polysubstance use is a serious public health concern across the globe (Morley KC. et al., 2017; Lyons et al., 2019; Zuckermann et al., 2019), especially among young adults and adolescents (Tomczyk et al., 2016; Silveira et al., 2019; Willis et al., 2019; Zuckermann et al., 2019). Among the adolescents, the common polysubstance use comprised cigarettes/E-cigarettes/tobacco, alcohol, and marijuana (Tomczyk et al., 2016; Zuckermann et al., 2019, 2020; Tan et al., 2020). Systematic analysis of data from the US, United Kingdom, France, Germany, and Australia associated benzodiazepine with four-fold greater odds of misuse and six-fold greater odds of abuse with prescription opioid analgesics (Morley KI. et al., 2017). Data from the National Survey on Drug Use and Health (2015–2018; 18–64 years old) revealed that the prevalence of opioid and methamphetamine use was higher among those from the age group 18–49 (Shearer et al., 2020). In the US, methamphetamine use was significantly increased among treatment-seeking opioid users, from 18.8% in 2011 to 34.2% in 2017 (Ellis et al., 2018). In line with this, an increase in methamphetamine use was reported among primary treatment admissions, from 1 in 50 in 2008 to 1 in 8 in 2017 (Jones et al., 2020). In Malaysia, a steep increase in polydrug abuse was reported, with 8,841 polydrug abusers in 2018, by 2019 it has increased to 15,166 polydrug abusers which is around a 71.5% increase in a year’s time (National Anti-Drugs Agency, 2019). Moreover, in the US, almost half of the psychostimulant use-related deaths involve opioids, and likewise, opioid use related-deaths involve methamphetamine co-use (Ihongbe and Masho, 2016; Lancet, 2018; Gladden et al., 2019; Kariisa et al., 2019; Compton et al., 2021).

Polydrug abuse refers to the fairly common activity where drug users combine the desired effects of multiple different drugs in one administration or on separate occasions. The combination that is most popular among polydrug users is the co-use of stimulants and opioids, which is known as “speedball: combination of opioids and cocaine” (Trujillo et al., 2011) or “goofball: combination of opioids and methamphetamine” (Glick et al., 2021). Individuals with OUD often co-use methamphetamine through separate use or co-injection (Al-Tayyib et al., 2017), to balance the two drugs’ relative effects, attaining a synergistic high or mitigate the risk of overdose or withdrawal (Ellis et al., 2018; Palmer et al., 2020; Baker et al., 2021). Patients taking medications for OUD, use methamphetamine to attain an alternative high to opioids and/mitigate the sedative effects of the medications (McNeil et al., 2020; Palmer et al., 2020). Polydrug abuse also refers to the sequential use of drugs, which is the consumption of a substance after the peak effect of another substance, reportedly to alleviate withdrawal symptoms or to prolong a state of euphoria (Preston et al., 2016). Combinations most popularly included stimulant and depressant substances (Rigg and Ibañez, 2010; Silva et al., 2013) with the main motivation behind this sequential combination being the alleviation of withdrawal symptoms. However, the sequential polydrug combination does not exclude substances of the same class which aim to ease the effects of the drug (Lankenau et al., 2012; Kecojevic et al., 2015). Prolonging a high also was a motivation behind the sequential use of stimulants and opioids, which manages the opposing psychotropic effects (Valente et al., 2020). Moreover, it was reported that methamphetamine users with a history of polysubstance use (such as heroin, ketamine, and ecstasy) are more prone to develop anxiety symptoms during the early period of abstinence (Su et al., 2017). In line with this, polydrug use was associated with anxiety and depression by a 10-years prospective study (Burdzovic Andreas et al., 2015). A study involving psychostimulant-dependent patients with a history of polydrug use revealed that the severity of negative symptoms in psychostimulant-associated psychosis is not related to the psychostimulant use, but rather due to the use of opioids (Willi et al., 2016). Furthermore, it was also reported that co-use of methamphetamine and morphine results in differential physical symptoms compared to the use of morphine or methamphetamine alone. For instance, co-used patients reported increased catecholaminergic hyperstimulation of respiratory, cardiovascular, and peripheral nervous systems, and more severe neuropsychiatric symptomatology (Liu et al., 2015).

Although there have been a number of preclinical studies that attempt to characterize the polydrug abuse phenomenon, there is still insufficient evidence to completely understand the behavioral and neurochemical consequences that come with it. Chronic administration of morphine and methamphetamine increased the incidence of jumping behavior (Kaka et al., 2014), where morphine assigned rats were given cumulative doses of 5, 10, 20, 30, and 40 mg/kg per day within 5 days while methamphetamine was assigned rats were given cumulative doses of 1, 2, 4, 6 and 8 mg/kg per day for 5 days, and lastly, on day 6, a combination of 8 mg/kg methamphetamine and 40 mg/kg morphine was injected. It is indicative of an attempt to escape the test chamber due to withdrawal-induced anxiety and stress (Liu et al., 1999). Manifestation of withdrawal symptoms in the methamphetamine or morphine alone administered animals were dissimilar to the animals exposed to both methamphetamine and morphine. None of the methamphetamine-administered animals displayed escape behaviors and other behaviors such as ptosis and chewing were more pronounced in the morphine-treated animals (Kaka et al., 2014). The co-use of drugs often masks the unwanted effects of the other drug. In line with this, it was reported that the co-use of morphine and low dose methamphetamine (7.5 mg/kg and 1.0 mg/kg respectively) caused sensitization of the opioid receptor system with the psychostimulant masking the sedative effects of morphine (Ridzwan et al., 2018). The effects of methamphetamine and morphine co-use depend on the drugs’ dose and behaviors assessed, and very often synergistic effects of the drugs have been reported with concurrent co-use. An acute combination of morphine (5 mg/kg) and methamphetamine (1 mg/kg) injected subcutaneously resulted in more than twice of ambulation and more than 50% of rearing than the animals administered with each drug alone, indicating synergistic effects from the co-use (Trujillo et al., 2011). Furthermore, it was also reported that methamphetamine (0.032 mg/kg/infusion) had no reinforcing effects on rats withdrawn from morphine or morphine-dependent rats, whereas fentanyl produced high reinforcing effects on morphine withdrawn animals, and reduced effects on morphine-dependent animals. These results suggest that the reinforcing effects of methamphetamine are independent of the withdrawal or dependence state of opioid use (Seaman et al., 2021). Likewise, morphine (0.75 mg/kg i.p.) also produced synergistic effects on methamphetamine-induced (5 mg/kg i.p.) conditioned place preference and sensitization of stereotyped behaviors along with methamphetamine (Lan et al., 2009).

Neurological Changes in Drug Dependent Brains

Addiction experts at the World Health Organization proposed in 1950 that drug addiction is primarily characterized by psychological dependence, regardless of the type of drug (Eddy and Isbell, 1959). Due to this, early psychological hypotheses linked addiction to symptoms like psychic tolerance (which was thought to be the source of increasing drug consumption) and abstinence agony (also known as withdrawal syndrome) (the presumed main obstacle to abstinence) (Solomon and Corbid, 1973). For many years, researchers speculated that the mesotelencephalic dopamine system was responsible for the rewarding effects of both opiates (such as heroin and morphine) and psychostimulants, building on the discovery that electrical stimulation of certain brain areas may produce reward (for example, cocaine, amphetamine, and methamphetamine) (Wise, 1978; Di Chiara and Imperato, 1988). Motivational effects of drug-associated signals and psychomotor sensitization to addictive substances were both linked to this system (Stewart et al., 1984). Using these neuropharmacological findings, the 1987 psychomotor stimulant theory of addiction and later theories highlighted shared psychobiological foundations for addiction, spanning drug classes, were based on these neuropharmacological breakthroughs (Wise and Bozarth, 1987; Badiani et al., 2011).

Opioid Dependence

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).

Methamphetamine Dependence

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).

Neurochemical Changes in Drug Dependent Brains

Dopamine

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 Receptors

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.

Polydrug Use

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).

Pharmacotherapy for Opioid Use Disorder and Methamphetamine Use Disorder

Opioid Use Disorder

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).

TABLE 1. Current treatment in opioid dependence.

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).

Methamphetamine Use Disorder

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).

TABLE 2. Current treatment in methamphetamine dependence.

Polysubstance Abuse

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).

TABLE 3. Current treatment in polydrug dependence.

Conclusion

The prevalence and risk associated with polydrug use are threats to the current public health resources worldwide. Thus, improving and pooling the understanding of mechanisms behind individual drugs and their combined use is essential to accurately reflect their effects on the neurochemical systems. However, this knowledge is still limited, especially in its polydrug combinations that can contribute to unique addiction potential and the development of addictive behaviors. It is important to appreciate novel preclinical experiments that investigate the pathophysiology and pharmacotherapy targeting the mono and polydrug abuse of morphine and methamphetamine. Given how complex addiction as a disease is with many powerful elements playing their roles, we need to understand the mechanisms behind the relationship between polydrug abuse and addiction to determine better and more effective treatments for this ongoing public health crisis.

Introduction

Dependence on drugs and alcohol presents a significant global challenge, impacting society, economies, and public health. The number of people using substances like methamphetamine and opiates continues to rise rapidly, despite strict drug laws. Recent data indicates a sharp increase in hospitalizations and deaths related to stimulants, surpassing even prescription opioid overdose rates. Similarly, opioid overdoses and related deaths have escalated. A concerning trend is the increasing co-use of psychostimulants and opioids, with nearly half of stimulant-related deaths involving opioids, and a rise in opioid deaths involving methamphetamine. Addressing drug dependence is costly; while an estimated $35 billion is spent annually on treating a fraction of global drug users, the actual cost to treat all users could reach $200 billion per year. The societal cost of untreated and ongoing drug use far exceeds treatment investment.

For opioid dependence, one well-studied treatment option is methadone maintenance therapy (MMT). MMT aims to reduce harm and has shown effectiveness in lowering high-risk behaviors. However, some studies suggest that MMT may not significantly improve long-term quality of life and requires lifelong commitment. Other medications, such as buprenorphine or buprenorphine-naloxone, are primarily used in private settings due to their cost. Buprenorphine acts similarly to methadone, while naloxone is an opioid blocker often used to reverse overdoses. There have been reports of buprenorphine combinations being injected illicitly, which can increase opioid dependence. Oral naltrexone for opioid dependence has been ineffective due to poor adherence. Naltrexone implants have shown some positive results for opioid or polydrug abuse, but their long-term effectiveness and potential for overdose have not been fully explored.

Currently, no consistently effective drug treatments exist for methamphetamine use disorder (MUD). While some studies have shown positive outcomes with certain medications like dexamphetamine, methylphenidate, naltrexone, and topiramate, others, such as antidepressants, have been less effective. Individual studies have reported that buprenorphine, N-acetylcysteine, and methylphenidate may reduce methamphetamine craving, but drugs like bupropion, modafinil, and varenicline have shown little or no efficacy in treating methamphetamine dependence.

This review examines the changes in behavior and brain chemistry associated with dependence on morphine and methamphetamine, both separately and in combination. It also outlines recent advancements in medication and other treatments for single and combined opioid and methamphetamine use.

Opioid Use Disorder

Opioid abuse often begins with over-prescription for pain relief, a problem worsened by the increasing availability of inexpensive opioids. People can develop tolerance to opioids, needing higher doses to achieve the same pain relief. This can lead to severe side effects, including withdrawal symptoms and dangerous breathing suppression. Globally, North America has the highest rates of opioid use. Many individuals report misusing prescription opioids, and common illicit opioids include heroin, fentanyl, and morphine. Opioid overdoses account for a significant number of deaths worldwide, a rate exacerbated by events such as the COVID-19 pandemic.

Tolerance means needing more of the drug to get the same effect. People can become dependent due to severe withdrawal symptoms, which include physical effects like abdominal pain, nausea, diarrhea, and muscle aches. Psychological dependence refers to intense craving for the drug, either to relieve withdrawal or for its pleasant effects. Abstinence often leads to negative feelings like anxiety and agitation, driving the urge to relapse. Opioid-dependent individuals may also experience increased impulsivity and difficulty with decision-making, along with reduced ability to feel pleasure.

Animal studies using models of opioid dependence show behaviors similar to human symptoms, such as depression-like states, increased anxiety, and impulsive actions during withdrawal. These models also suggest that opioids can impair learning and memory.

Fentanyl is a particularly dangerous opioid linked to many fatalities. It is significantly more potent than heroin and morphine and is often mixed into other drugs to increase their potency. Fentanyl use can cause drowsiness, euphoria, and respiratory depression, along with severe withdrawal symptoms like diarrhea, sweating, and bone pain. Animal studies confirm that fentanyl affects the brain's immune response and reward system. Chronic use can lead to brain changes that contribute to addiction, anxiety during withdrawal, and cognitive problems.

Heroin is another major opioid associated with numerous overdose deaths, and its co-use with other prescription drugs is increasing, often due to its lower cost and easier availability. Heroin withdrawal symptoms include restlessness, insomnia, muscle pain, and depression, peaking within days and lasting for up to ten days. Chronic heroin use can impair learning and memory and reduce motivation, potentially by causing damage to brain cells.

Methamphetamine Use Disorder

Methamphetamine is a powerful stimulant that is widely abused, particularly in its crystal form. Its use is a significant public health concern globally, with high rates reported in North America and Southeast Asia.

Clinical observations show that chronic methamphetamine use is linked to withdrawal symptoms such as fatigue, sleep disturbances, agitation, depression, and anxiety. Anxiety and depression can be severe, especially early in withdrawal, and longer methamphetamine use is associated with a higher likelihood of depression. Symptoms like craving and sleep problems can persist for up to four weeks after stopping use. Increased impulsivity is also common among methamphetamine users during abstinence, which can drive continued drug use. Methamphetamine dependence affects cognitive abilities, including visual memory, attention, learning, and decision-making. These cognitive impairments may not improve significantly even after several months of abstinence.

Animal studies involving various methamphetamine dosing schedules have consistently shown anxiety and depression-like behaviors during withdrawal. However, findings on changes in animal movement during withdrawal have varied, likely due to differences in animal strains, drug doses, and administration methods used in the studies.

Co-Abuse of Opioid and Methamphetamine

Using multiple substances together, known as polysubstance use, is a major public health concern, especially among young adults. Common combinations include tobacco, alcohol, and marijuana. There has been a notable increase in the co-use of opioids and methamphetamine. In the United States, methamphetamine use among opioid users seeking treatment has risen significantly. Similarly, many drug-related deaths involve the co-use of stimulants and opioids.

Polydrug abuse refers to using different drugs together or at different times. A common combination is stimulants and opioids, sometimes called "speedball" (opioids and cocaine) or "goofball" (opioids and methamphetamine). Individuals may combine these drugs to achieve a stronger high, balance their effects, or reduce the risk of overdose or withdrawal. People undergoing opioid addiction treatment might use methamphetamine for an alternative high or to counter the sedating effects of their medication. Sequential use, where one drug is taken after another, is often done to alleviate withdrawal symptoms or prolong a euphoric state. Polydrug use is linked to increased anxiety and depression, and in some cases, the severity of negative symptoms in psychosis related to stimulant use may be influenced by opioid co-use. Patients who co-use methamphetamine and morphine have reported more severe physical symptoms, including increased stimulation of the respiratory, cardiovascular, and nervous systems, as well as more intense mental health symptoms.

While preclinical studies have explored polysubstance use, a complete understanding of its behavioral and brain chemistry consequences remains limited. Combining morphine and methamphetamine has been shown to produce stronger rewarding effects than either drug alone, leading to behaviors indicative of anxiety and stress during withdrawal. The effects of co-use can depend on the specific drug doses and behaviors being studied, and often, synergistic effects are observed. For instance, low doses of morphine and methamphetamine together can cause heightened activity and may mask the sedative effects of morphine. The reinforcing effects of methamphetamine appear to be independent of opioid withdrawal or dependence.

Neurological Changes in Drug Dependent Brains

Early theories of addiction focused on psychological dependence, tolerance, and withdrawal. Later, research revealed that the brain's dopamine system, which is involved in reward, plays a key role in the effects of both opiates and stimulants. These discoveries led to theories that highlighted shared brain-based reasons for addiction across different drug types.

Opioids cause significant changes in the brain. In individuals not dependent on opioids, acute use increases activity in brain regions associated with reward. However, during opioid withdrawal, activity in reward and association areas can increase, while activity in areas for sensory integration and attention decreases. Long-term opioid dependence is linked to reduced connectivity in certain brain networks. The severity of drug use and withdrawal symptoms are often connected to how the brain's reward areas respond to drug cues. These neurological and behavioral changes can also evolve over time during abstinence. Heroin, for example, impairs brain areas critical for decision-making and impulse control, leading to problems with cognitive function and weakened executive control. Fentanyl affects dopamine processing and brain communication networks, resulting in reduced function in motor, cognitive, and sensory areas, while increasing activity in reward-related regions. Chronic fentanyl use can also cause significant cognitive damage, including memory loss and reduced brain volume in certain areas.

Methamphetamine causes widespread brain damage and cognitive decline, affecting regions involved in cognitive control and decision-making, such as the prefrontal cortex and anterior cingulate cortex. Chronic methamphetamine use leads to loss of gray matter and reduced hippocampal size, which are linked to cognitive impairment. While some studies suggest cognitive function can improve after several months to a year of abstinence, others indicate that impairments can persist even after more than a month. Adolescent brains are particularly vulnerable to methamphetamine's effects, especially on the frontostriatal system. Methamphetamine dependence is also associated with psychosis, which is linked to altered activity in specific brain regions.

Neurochemical Changes in Drug Dependent Brains

Brain chemistry changes are central to addiction, especially involving the dopamine system, which connects to brain areas like the striatum, hippocampus, and prefrontal cortex. Dopamine receptors, D1 and D2, play different roles in how the brain responds to rewards and punishments.

When opioids are first used, they increase dopamine release in the brain's reward system, contributing to their reinforcing effects. However, long-term opioid use reduces dopamine release, leading to a "reward deficiency syndrome" where normal pleasures are dulled. The brain may try to compensate by increasing dopamine receptor levels. Stimulants like methamphetamine cause an even greater flood of dopamine, but chronic use can lead to a general reduction in dopamine receptors. These changes can result from the loss of dopamine neurons or damage to nerve endings caused by methamphetamine. Such deficits in dopamine systems contribute to cravings and relapse, as the brain's natural dopamine levels are no longer sufficient for stimulation. Long-term methamphetamine use also reduces dopamine transporters in various brain regions, which may explain the impaired impulse control seen in dependent individuals.

Opioids interact with specific receptors in the brain: mu (MORs), kappa (KORs), and delta (DORs). MORs are primarily involved in the motivational aspects of drug use and are linked to reward. KORs, however, are part of an "anti-reward" system that mediates negative emotional states such as depression, stress, and aversion, especially during withdrawal. The balance between MORs (which boost dopamine) and KORs (which inhibit dopamine) influences the progression from casual drug use to dependence. Chronic opioid use can alter the number and activity of MORs, and it can reduce the body's natural pain-relieving chemicals. This can make opioid receptors less responsive, leading to tolerance and addiction. DORs are not primarily associated with drug reward but are involved in learning and memory and can help alleviate negative moods. Chronic opioid use can reduce DORs in areas like the hippocampus, contributing to memory problems. Methamphetamine also affects opioid receptors, and its impact on anxiety during withdrawal may be linked to sustained increases in MORs. The interaction between opioid and dopamine systems is crucial; dopamine receptor activation is necessary for the increased expression of MORs in the presence of stimulants, indicating how these systems work together to mediate the rewarding effects of drugs. Higher doses of methamphetamine can produce pain relief similar to morphine, and this effect is likely mediated through MORs.

When methamphetamine and morphine are used together, they can alter the brain and behavior differently than either drug alone. Studies show that combining these drugs can produce greater rewarding effects and lead to higher dopamine levels in brain areas like the nucleus accumbens, increasing their reinforcing potential. The combination also creates unique changes in how dopamine is processed, affecting different brain systems in distinct ways compared to single drug use. For combinations like heroin and cocaine ("speedball"), the increase in nucleus accumbens dopamine is a key factor, with different dopamine receptors playing roles in enhancing or inhibiting the drug's effects.

Pharmacotherapy for Opioid Use Disorder and Methamphetamine Use Disorder

For opioid use disorder, medications like methadone and buprenorphine are primary treatments. Methadone maintenance therapy (MMT), taken orally, can improve quality of life and reduce the spread of blood-borne diseases. However, careful management is needed due to potential interactions with other medications, especially in patients with co-occurring health conditions like HIV. Buprenorphine, often combined with naloxone to prevent misuse, helps people maintain abstinence and stay in treatment. However, illicit injection of buprenorphine combinations has occurred. The co-use of methamphetamine is common among opioid-dependent patients and can complicate treatment, sometimes leading to opioid relapse or non-retention in buprenorphine therapy. Specific challenges exist for treating fentanyl dependence, but approaches like buprenorphine micro-dosing show promise. Importantly, psychosocial interventions such as Contingency Management (CM) and Cognitive Behavioral Therapy (CBT) are crucial alongside medication, enhancing treatment attendance and long-term abstinence.

For methamphetamine use disorder, various medications have been explored. MMT is sometimes prescribed for chronic methamphetamine users. Buprenorphine may help reduce methamphetamine cravings more effectively than some other drugs like bupropion, though bupropion has not consistently improved abstinence rates. Other drugs like N-acetyl cysteine (NAC) have shown some promise in suppressing craving, but their impact on overall methamphetamine use is unclear. Modafinil has shown mixed results. Varenicline has not been effective, but methylphenidate appears safe and can reduce methamphetamine use, craving, and depressive symptoms. Behavioral therapies are very important for methamphetamine dependence. Cognitive Behavioral Therapy (CBT) can reduce dependence, improve well-being, and lessen cravings. Comprehensive programs like the Matrix Model, which combine CBT with motivational interviewing, family, and group therapy, have been found to be more effective in increasing methamphetamine abstinence compared to CBT alone.

For polysubstance use, integrated treatment approaches are needed. Naltrexone implants have shown potential in retaining patients and reducing heroin and methamphetamine use. Combinations of buprenorphine and naltrexone have been studied to reduce relapse in co-use of substances like cocaine and morphine. Contingency management combined with buprenorphine maintenance has also been explored for polydrug abusers. High-dose methadone maintenance has been found to reduce drug-seeking behaviors for both heroin and cocaine. Interestingly, studies have shown that cooling the body shortly after a combined overdose of methamphetamine and morphine can significantly reduce toxicity and lethality, highlighting a critical window for intervention.

Conclusion

The widespread and risky nature of polysubstance use poses a significant threat to global public health resources. Therefore, it is essential to deepen our understanding of how individual drugs and their combinations affect the brain's chemistry. This knowledge is currently limited, particularly regarding polydrug combinations and their unique potential for addiction and the development of addictive behaviors. Valuing new preclinical research that explores the causes and treatments for single and combined morphine and methamphetamine abuse is crucial. Given the complexity of addiction as a disease, with many powerful contributing factors, a thorough understanding of the relationship between polydrug abuse and addiction is necessary to develop more effective treatments for this ongoing public health crisis.

Introduction

Drug and alcohol dependence poses significant global challenges to society, the economy, and public health. The number of people using methamphetamine and opiates worldwide continues to increase rapidly, even with strict drug laws in place. Recent data shows a sharp rise in hospitalizations and deaths related to stimulants, now exceeding deaths from prescription opioid overdoses. Opioid overdoses and related deaths have also increased. A major concern is the growing trend of polysubstance use, where nearly half of stimulant-related deaths involve opioids, and opioid-related deaths frequently involve methamphetamine. Treating an estimated 4.5 million drug users worldwide costs approximately $35 billion annually, yet this only covers about one-sixth of those who need help. If all individuals with drug dependence sought treatment, the estimated global cost could reach $200 billion. Research indicates that the costs associated with untreated and ongoing drug use are far greater than the investment in treatment, encompassing both direct expenses like inpatient treatment and emergency services, and indirect costs such as research for prevention and treatment.

Opioid dependence currently has some of the most extensively researched treatment options. Methadone Maintenance Therapy (MMT) is a common harm reduction strategy for opiate addiction; while some reports show it reduces high-risk behaviors, others suggest it may not significantly improve patients' long-term quality of life and often requires a lifelong commitment. Other medications, such as buprenorphine or buprenorphine-naloxone combinations, are typically used as maintenance therapy in private settings due to their higher cost. Buprenorphine acts as an opioid agonist, while naloxone is a rapid-acting opioid antagonist often injected to reverse opioid overdoses. In some countries, illicit injection of these combinations has led to increased opioid dependence. Oral naltrexone treatment for opioid dependence is often ineffective because individuals struggle to adhere to it, though naltrexone implants have shown some positive results in treating opioid or polydrug abuse. However, the long-term clinical effectiveness of these implants and the potential risk of opioid overdose associated with them have not been fully studied.

Currently, there are no highly effective medication-based treatments (pharmacotherapy) for Methamphetamine Use Disorder (MUD). Reviews of existing research show some positive results with medications like dexamphetamine, methylphenidate, naltrexone, and topiramate. In contrast, antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, have been less effective in managing MUD. Specific clinical studies have indicated that buprenorphine, N-acetylcysteine, and methylphenidate may help reduce methamphetamine cravings. However, other studies have found that drugs like bupropion, modafinil, and varenicline are not effective for treating methamphetamine dependence.

This review examines the behavioral and brain chemistry changes associated with dependence on morphine and methamphetamine, both individually and in combination, in humans and animals. The review also outlines recent progress in medication treatments for single and combined use of opioids and methamphetamine, covering both clinical and preclinical research.

Opioid Use Disorder

Origins of opioid abuse often stem from over-prescription for pain relief and the increasing availability of low-cost opioids. Patients develop tolerance, requiring higher doses, which increases vulnerability to severe side effects like withdrawal and respiratory depression. North America has the highest prevalence of opioid use globally. Surveys show nearly 1 in 5 individuals report abuse and 1 in 4 misuse prescription opioids. Heroin, fentanyl, and morphine are commonly used, alongside methadone, buprenorphine, codeine, tramadol, oxycodone, and hydrocodone. Globally, opioid overdoses cause approximately 115,000 deaths annually, with the COVID-19 pandemic further increasing this fatality rate.

Morphine abuse leads to addiction, marked by tolerance—the need for increased doses to achieve the same effect. Tolerance is defined by specific daily opioid dosages, such as 60 mg/day of oral morphine for a week. Dependence results from severe withdrawal symptoms like abdominal pain, nausea, and piloerection. Psychological dependence involves craving the drug to alleviate withdrawal or for its pleasurable effects, leading to a high risk of relapse. Opioid-dependent individuals also experience heightened impulsivity, impaired planning, and increased anhedonia (inability to feel pleasure). Withdrawal symptoms significantly drive continued abuse and hinder discontinuation efforts.

Animal models help mimic human psychological states in the presence or absence of substances, establishing behavioral parameters for opioid abuse. In opioid-dependent animal models, depressive-like behaviors, such as decreased social interaction and increased immobility, become significant after prolonged withdrawal. Anxiety is another prominent symptom during abstinence, evidenced by increased anxiety-like behaviors in animal tests. Impulsive behavior, including poor inhibitory control and impulsive decision-making, also accompanies abstinence, with the opioid system playing a key role. Morphine exposure in animals also increases motor impulsivity and causes deficits in learning and memory.

Fentanyl abuse has led to numerous fatalities globally, with rising misuse of prescription opioids in the United States. Fentanyl and its analogs are highly potent opioid agonists, often found as cutting agents in heroin to increase its strength, and can cause drowsiness, respiratory depression, and anxiety, alongside withdrawal symptoms such as diarrhea, bone pain, and shivers. Studies in rats show that fentanyl self-administration disrupts the brain's immune response, potentially contributing to relapse and neurocognitive disorders. Chronic fentanyl use in animals can lead to aversive responses and severe deficits in brain reward function during withdrawal, with some research on vaporized fentanyl suggesting the development of addiction-like states.

Heroin overdoses account for significant fatalities in the United States, with a notable increase in polydrug use involving heroin and other prescription drugs. Factors like the high cost and low availability of heroin drive individuals to seek cheaper, longer-lasting highs through polydrug abuse. Heroin withdrawal symptoms include restlessness, insomnia, muscle pain, and depression, peaking within 48-72 hours and lasting 5-10 days. Chronic heroin use impairs spatial learning and memory and can lead to motivational deficits, manifesting as a reduced drive to pursue rewards.

Methamphetamine Use Disorder

Methamphetamine is a powerful psychostimulant widely abused recreationally, despite its limited medical uses for attention deficit hyperactivity disorder and obesity. Its abuse, especially in crystalline form, remains a significant public health concern, with rapidly increasing use in East and Southeast Asia. While North America reports the highest prevalence of Amphetamine Type Stimulant (ATS) abuse, Malaysia shows a particularly high percentage of ATS use among its drug abusers.

Chronic methamphetamine use is clinically linked to withdrawal symptoms including fatigue, sleep disturbances, dysphoria, agitation, increased appetite, depression, and anxiety. Anxiety and depression are particularly severe during early withdrawal, with longer use correlating with higher rates of depression and co-occurring anxiety and psychosis. Craving and sleep disturbances can persist for up to four weeks post-abstinence, and increased impulsivity is also common. Methamphetamine dependence impairs cognitive abilities such as visual memory, attention, working memory, and decision-making, and these cognitive deficits often do not significantly improve even after a month of abstinence.

Researchers use various methamphetamine dosage regimens in animal models (mice and rats) to induce withdrawal. Withdrawal from chronic methamphetamine exposure in these models leads to behavioral changes like anxiety and depressive symptoms. Observations regarding changes in locomotion during withdrawal vary, likely due to differences in animal strains, methamphetamine administration methods, doses, and durations of use.

Co-Abuse of Opioid and Methamphetamine

Polysubstance use, particularly among young adults and adolescents, is a significant global public health concern. Common combinations include tobacco products, alcohol, and marijuana, while other studies link benzodiazepine use with increased misuse of prescription opioid analgesics. Data from the United States indicates a rising prevalence of opioid and methamphetamine co-use, especially among younger adults, and a sharp increase in methamphetamine use among individuals seeking treatment for opioid use disorder. This trend is also evident in Malaysia, with a significant rise in polydrug abusers, and almost half of stimulant-related deaths in the U.S. now involve opioids, with a similar increase in opioid-related deaths involving methamphetamine co-use.

Polydrug abuse involves combining various drugs, often to achieve desired effects or manage symptoms. Examples include "speedball" (opioids and cocaine) or "goofball" (opioids and methamphetamine), used to balance drug effects, achieve a synergistic high, or reduce overdose/withdrawal risks. Sequential use, where one substance is consumed after another, often aims to alleviate withdrawal symptoms or prolong euphoria. Polydrug users frequently report increased anxiety and depression, and co-use of methamphetamine and morphine can lead to more severe physical and neuropsychiatric symptoms compared to using either drug alone. While preclinical studies are limited, findings suggest that co-use can lead to greater rewarding effects, mask unwanted drug effects, and cause synergistic changes in behaviors and neurochemical systems.

Neurological Changes in Drug Dependent Brains

Early theories in addiction proposed it was primarily characterized by psychological dependence, driven by psychic tolerance (leading to increased consumption) and withdrawal syndrome (hindering abstinence). Researchers later linked the mesotelencephalic dopamine system to the rewarding effects of both opiates and psychostimulants, also associating this system with motivational effects and psychomotor sensitization to addictive substances. These neuropharmacological findings led to theories highlighting shared biological bases for addiction across different drug classes.

Acute morphine administration to drug-naive individuals increases activity in brain regions associated with reward, such as the amygdala and nucleus accumbens. Conversely, acute opioid withdrawal in healthy subjects leads to increased neural activity in reward-prediction areas, while decreasing activity in regions related to sensorimotor integration. Chronic opioid-dependent patients show reduced connectivity in the midbrain-thalamic grey matter, and the severity of drug use and withdrawal symptoms correlates with neural responses to drug cues in key reward areas like the orbitofrontal cortex and amygdala. Neurological and behavioral changes in opioid-abstinent patients are time-dependent; recently withdrawn individuals show reduced pleasure from natural rewards, increased drug-related cues, and higher stress hormone levels compared to those abstinent for several months, suggesting brain adaptation over time.

Heroin use is strongly linked to impulsivity and poor decision-making, impacting brain regions critical for cognitive functions. Studies show heroin-dependent individuals have significant functional changes and impaired white matter structural networks in areas like the prefrontal cortex and cingulate gyrus. This dysregulation in brain regions involved in reward, motivation, memory, and control compromises functional connectivity and executive control. Such neurological changes manifest as increased impulsivity and impaired decision-making, as observed in various cognitive assessments.

Acute fentanyl exposure can decrease dopamine transporter activity in areas like the striatum and basal ganglia, though these changes may not persist after a drug-free period. In non-human primates, fentanyl self-administration reduces functional connectivity in brain regions associated with motor and cognitive functions, while increasing connectivity in reward-processing areas like the nucleus accumbens, similar to other addictive opioids. Chronic fentanyl intake can also lead to cognitive impairment, including acute amnestic syndrome, with observable loss of volume in hippocampal subfields.

Methamphetamine use frequently causes cognitive deterioration, affecting brain regions vital for cognitive control and decision-making, such as the prefrontal cortex and anterior cingulate cortex. Chronic intake leads to significant gray matter deficits and reduced hippocampal size, correlating with observed cognitive impairments. While some studies report cognitive improvement after prolonged abstinence (six months to one year), others suggest that even after over a month, deficits may persist, indicating the need for longer abstinence to reverse chronic effects. Adolescent brains are particularly vulnerable to methamphetamine-induced alterations, especially in the frontostriatal system. Withdrawal from chronic methamphetamine also remodels the brain's functional architecture, and psychosis in dependent individuals is linked to altered activity in specific brain areas like the precentral gyrus and putamen.

Neurochemical Changes in Drug Dependent Brains

The dopaminergic neurotransmitter system, which involves D1 and D2 receptors, is crucial in addiction, innervating brain regions like the striatum, hippocampus, and prefrontal cortex. Variations in these receptors' outputs lead to different responses to rewards, unpleasant stimuli, and the prediction of both.

Acute opioid use increases dopamine release in the striatum, contributing to the drug's reinforcing effects. However, prolonged opioid exposure often dampens striatal dopamine release, leading to a "hypodopaminergic" state associated with a reduced sense of satisfaction. Conflicting findings exist regarding long-term dopamine levels in chronic opioid users, though some postmortem studies suggest an upregulation of D1 and D2 dopamine receptors in response to reduced dopamine.

Psychostimulants induce a greater dopamine release in the ventral striatum compared to opioids, primarily by directly affecting dopamine transporters. Chronic stimulant use generally leads to a downregulation of dopamine receptors and transporters, causing functional deficits in dopamine-rich brain areas. These changes may explain craving and relapse, as the brain's natural dopamine levels become insufficient for normal stimulation. While most studies report reduced dopamine transporter levels in various brain regions after chronic methamphetamine use, suggesting a mechanism for impaired inhibitory control, some research has found no such effects in certain areas.

Opioid receptors, including mu (MORs), kappa (KORs), and delta (DORs), play crucial roles in drug dependence. MORs mediate motivational and rewarding effects, while KORs contribute to negative affective states during withdrawal by inhibiting dopamine release. Prolonged opioid use can reduce the body's natural endorphin production and downregulate MORs, increasing dependence and tolerance. DORs, linked to learning and memory, may also be affected, contributing to cognitive deficits seen in opioid-dependent individuals. Additionally, methamphetamine can influence opioid receptors, leading to changes in MOR expression that correlate with anxiety during withdrawal, and its rewarding effects may involve interactions between the dopaminergic and opioid systems.

Co-use of methamphetamine and morphine can lead to significantly greater rewarding effects and higher conditioned place preference compared to either drug alone, even at low doses, indicating increased reinforcing potential. Repeated co-administration has been shown to elevate dopamine levels in the nucleus accumbens more than individual drugs, further supporting enhanced reinforcing effects. The combined use of these drugs can lead to complex and differential changes in striatal dopamine levels and turnover, distinct from the effects of single drugs, highlighting varied impacts on the brain's mesolimbic and nigrostriatal dopamine systems. Similar interactions are observed with other polydrug combinations, such as heroin and cocaine, where low doses can additively increase nucleus accumbens dopamine, and different dopamine receptor subtypes play specific roles in enhancing or inhibiting the reinforcing effects of these drug combinations.

Pharmacotherapy for Opioid Use Disorder and Methamphetamine Use Disorder

Methadone Maintenance Treatment (MMT) effectively improves quality of life and reduces disease transmission for opioid-dependent individuals, though it carries safety concerns due to drug interactions and potential adverse effects. Buprenorphine, often combined with naloxone, helps sustain abstinence, but illicit injection of these combinations can increase dependence. Methamphetamine use is common among OUD patients, sometimes linked to lower retention in buprenorphine treatment as patients may use it to balance drug effects or mitigate sedative effects of medications.

MMT has shown efficacy for fentanyl abuse, though relapse rates remain high. Newer strategies like buprenorphine micro-dosing offer gradual induction with milder withdrawal. Psychosocial interventions, including Contingency Management (CM) and Cognitive Behavioral Therapy (CBT), are vital complements to medication, improving treatment attendance, abstinence duration, and overall psychological well-being.

For Methamphetamine Use Disorder (MUD), buprenorphine has shown promise in reducing cravings, while bupropion has not consistently increased abstinence. N-acetyl cysteine (NAC) shows potential for craving reduction, but its effect on actual drug use is less clear, and modafinil has yielded mixed results. In contrast, sustained-release methylphenidate has been found safe and effective in reducing methamphetamine use, cravings, and depressive symptoms.

Cognitive Behavioral Therapy (CBT) effectively reduces methamphetamine dependence and improves psychological well-being, consistently leading to significant reductions in use and psychiatric symptoms. Multi-component treatments like the Matrix Model, integrating elements of CBT and Motivational Interviewing, are more effective in achieving methamphetamine abstinence compared to standard CBT alone.

For polysubstance use, naltrexone subcutaneous implants show promise in retaining patients and decreasing heroin and methamphetamine use. Combinations of buprenorphine and naltrexone can reduce relapse in models of combined drug use. High-dose methadone maintenance can also reduce drug-seeking behavior, and early cooling (hypothermia) has been shown to reduce the acute toxicity and lethality associated with methamphetamine and morphine co-administration.

Conclusion

The widespread prevalence and associated risks of polydrug use pose a significant threat to global public health resources. A deeper understanding of the mechanisms behind individual drugs and their combined effects is crucial, as current knowledge of polydrug combinations, their unique addiction potential, and their role in developing addictive behaviors remains limited.

Further preclinical research is essential to investigate the disease processes and medication treatments for both single and combined morphine and methamphetamine abuse. Given the complex nature of addiction, a comprehensive understanding of the mechanisms underlying polydrug abuse is vital to develop more effective treatments for this persistent public health crisis.

Introduction

Dependence on drugs and alcohol presents a significant global challenge, impacting societies, economies, and public health. Despite strict drug abuse laws, the number of people using methamphetamine and opiates continues to increase rapidly. Recent reports show a sharp rise in hospitalizations related to methamphetamine and deaths from stimulants, now surpassing deaths from prescription opioids. Similarly, opioid overdose rates have also climbed in recent years. A concerning trend is the rise in polysubstance use, where almost half of stimulant-related deaths involve opioids, and many opioid-related deaths involve methamphetamine.

Treating drug users comes with a high financial burden. It is estimated that the global cost for treating a small portion of drug users is billions annually. If all individuals dependent on drugs were to seek treatment, the cost would be considerably higher, representing a significant percentage of the global economy. Research indicates that the cost of untreated and ongoing drug use is far greater than the investment in treatment and prevention efforts.

Currently, treatment options for opioid dependence are the most thoroughly researched. Methadone maintenance therapy (MMT) is a common approach for managing opiate addiction. While some studies show it can reduce risky behaviors, others suggest it may not significantly improve the overall quality of life for patients in the long term, and it often requires a lifelong commitment. Other medications like buprenorphine or buprenorphine-naloxone are mainly used in private settings due to high costs. Naltrexone implants have shown some positive results for opioid and polydrug abuse, but their long-term effectiveness and potential risks are not yet fully understood.

For methamphetamine use disorder (MUD), there are currently no treatments with consistently strong outcomes. While some studies show mild positive results with certain medications, others, like antidepressants, have been largely ineffective. Some individual studies suggest drugs like buprenorphine may reduce methamphetamine cravings, but many others have shown no benefit. This review aims to describe the changes in the brain and behavior that occur with dependence on morphine and methamphetamine, both separately and in combination. It also covers recent advances in medical treatments for single and combined opioid and methamphetamine use.

Opioid Use Disorder

Opioid abuse often begins with prescriptions for pain relief, with the increasing availability of affordable opioids making the problem worse. Patients can develop tolerance, needing higher doses for the same effect, which then makes them vulnerable to severe side effects like withdrawal and breathing problems. Opioid use is most common in North America. Many people have reported misusing or abusing prescription opioid pain relievers. Heroin, fentanyl, and morphine are among the most frequently used opioids. Globally, opioid overdoses have caused numerous deaths, a number further worsened by the COVID-19 pandemic.

When someone becomes addicted to opioids like morphine, they develop tolerance, meaning they need more of the drug to get the same initial effect. This leads to physical dependence, where stopping the drug causes severe withdrawal symptoms such as abdominal pain, nausea, diarrhea, and generalized body aches. These physical symptoms are very uncomfortable and contribute to continued drug use.

Psychological dependence also plays a major role, as individuals crave the drug to relieve withdrawal symptoms or to experience its pleasurable effects. The unpleasant withdrawal symptoms make it very difficult to stop using, often leading to relapse. People dependent on opioids may also experience increased impulsivity, difficulty with planning, reduced pleasure from normal activities, and general anxiety and agitation.

Studies involving animals show that opioid dependence can lead to behaviors that resemble depression, anxiety, and impulsivity. These behaviors can persist even after the drug is stopped. For example, some animals show reduced social interaction and increased inactivity, reflecting a lowered mood. Others show heightened anxiety in certain tests, and many display poor control over their actions. These animal models help researchers understand the complex behavioral effects of opioid withdrawal.

Fentanyl, an opioid significantly more potent than heroin or morphine, has contributed to many fatalities, especially when mixed with other illicit drugs. It can cause drowsiness, euphoria, severe breathing problems, and a range of withdrawal symptoms like diarrhea, cramps, and anxiety. Research in animals shows that chronic fentanyl use can disrupt the brain's immune response, potentially contributing to ongoing opioid use disorder. It can also lead to impaired brain reward systems and cognitive issues, similar to other highly addictive opioids.

Methamphetamine Use Disorder

Methamphetamine is a powerful stimulant that is widely abused as a recreational drug, even though it has limited medical uses. Its crystal form is a growing public health concern, especially in East and Southeast Asia, and it has the highest reported abuse rates in North America.

Clinical observations link long-term methamphetamine use to withdrawal symptoms such as fatigue, sleep problems, low mood, agitation, and increased appetite. Anxiety and depression are often severe, especially in the early stages of withdrawal. People who have used methamphetamine for longer periods tend to have a higher risk of depression, often combined with anxiety and psychotic symptoms. Craving and sleep disturbances can continue for up to a month after stopping use. Increased impulsivity and difficulties with decision-making and inhibitory control are also common among individuals who have used methamphetamine, suggesting problems with how the brain processes rewards. Methamphetamine dependence can also affect cognitive abilities like visual memory, attention, learning, and executive function. Studies show that even after a month of not using, some individuals may still have impaired cognitive function.

Animal studies have explored methamphetamine withdrawal using different drug doses and durations. These studies show changes in behaviors like anxiety and depressive symptoms during withdrawal. However, the specific behavioral changes, such as changes in movement, can vary depending on factors like the type of animal used, how the methamphetamine was given, the dose, and the length of exposure. These differences highlight the complexity of studying drug dependence in animal models.

Co-Abuse of Opioid and Methamphetamine

Using more than one substance, known as polysubstance use, is a serious global health concern, particularly among young adults and adolescents. Combining prescription opioids with other drugs, like benzodiazepines, is common. In the United States, methamphetamine use has significantly increased among people seeking treatment for opioid addiction. This rise in combined use is also seen in drug-related deaths. For instance, almost half of stimulant-related deaths involve opioids, and many opioid-related deaths involve methamphetamine.

Polydrug abuse involves individuals combining the effects of different drugs, either at the same time or separately. Popular combinations include stimulants and opioids, sometimes called "speedball" (opioids and cocaine) or "goofball" (opioids and methamphetamine). People may use these combinations to balance the effects of the two drugs, achieve a stronger high, reduce the risk of overdose, or lessen withdrawal symptoms. For those receiving medication for opioid use disorder, some may use methamphetamine to get a different high or to counteract the sedative effects of their medication. Sequential use, taking one drug after another, is also common, often to relieve withdrawal symptoms or to prolong the effects of a high. People who use multiple drugs may be more likely to experience anxiety and depression.

While many preclinical studies investigate polydrug abuse, there is still limited understanding of its full behavioral and neurochemical consequences. Studies in animals show that combining morphine and methamphetamine can lead to different physical and behavioral symptoms than using either drug alone. For example, the combination can increase escape behaviors, suggesting heightened anxiety. One drug might also mask the unwanted effects of the other. The effects of combined use often depend on the specific doses and behaviors studied, but synergistic effects—where the combined impact is greater than the sum of the individual drugs—are frequently reported.

Neurological Changes in Drug Dependent Brains

Addiction is largely understood as a disorder driven by psychological dependence and changes within the brain. Early theories recognized that the brain's reward system, particularly the dopamine system, plays a key role in the rewarding effects of both opiates and stimulants. This system is also involved in the motivation to seek drugs and the development of sensitization, where repeated drug use leads to a stronger response over time.

For opioid dependence, acute use can lead to increased activity in the brain's reward areas, such as the amygdala and nucleus accumbens. During acute opioid withdrawal, there is increased activity in areas related to reward prediction and association, while activity decreases in regions involved in sensory and motor functions. Long-term opioid dependence can also reduce connections in brain regions like the midbrain and thalamus. Individuals with opioid dependence often show stronger brain responses to drug cues in reward-related areas, which is linked to the severity of their drug use and withdrawal symptoms. These brain changes can evolve over time during abstinence.

Heroin use, in particular, has been linked to impulsivity and poor decision-making due to its negative effects on cognitive brain regions. Brain imaging studies show that individuals dependent on heroin have significant changes in their prefrontal cortex and other areas, affecting white matter connections. These changes disrupt brain networks involved in reward, motivation, learning, and control, all crucial processes in addiction. This leads to weakened executive control, which shows up as increased impulsivity and impaired decision-making.

Fentanyl also impacts brain function. Acute use can reduce the activity of dopamine transporters in the striatum, a brain region involved in movement and reward. Chronic fentanyl use in animals has been shown to reduce functional connections in brain areas tied to motor function, cognition, and sensory processing, while increasing connections in reward-processing areas, similar to other addictive opioids. Long-term fentanyl use can also lead to cognitive problems, including memory loss and changes in brain volume in areas like the hippocampus.

For methamphetamine dependence, one of the most common brain changes is cognitive decline, affecting regions like the prefrontal cortex and anterior cingulate cortex, which are vital for cognitive control and decision-making. Chronic methamphetamine use can also cause a loss of gray matter in parts of the brain and reduce the size of the hippocampus, which is linked to memory and learning. While some studies suggest cognitive function can improve with long-term abstinence, it may take many months or even a year for brain function to normalize. Adolescent brains are particularly vulnerable to these changes. Furthermore, psychosis associated with methamphetamine use has been linked to altered activity in specific brain areas.

Neurochemical Changes in Drug Dependent Brains

The brain's dopamine system is crucial in addiction, connecting to many brain regions involved in reward, motivation, and decision-making. Dopamine receptors, particularly D1 and D2, are widely distributed in areas like the striatum, nucleus accumbens, and frontal cortex. Variations in how these receptors function can lead to different responses to rewards, unpleasant experiences, and the prediction of future rewards or punishments.

When someone first uses opioids, there is an increase in dopamine release in the striatum, which creates the drug's rewarding effects. However, long-term opioid use can reduce this dopamine release due to adaptations in the dopamine system. This reduced dopamine state, often called "reward deficiency syndrome," can make it difficult to feel satisfaction from natural rewards. Although some studies show conflicting results on overall dopamine levels, chronic opioid use can lead to an increase in dopamine receptor expressions in certain brain areas, potentially as a compensatory response.

Psychostimulants like methamphetamine cause a greater initial release of dopamine in the brain's reward centers compared to opioids. This is because stimulants directly affect dopamine transporters, either by blocking reuptake or by reversing dopamine transport. Long-term stimulant use can lead to a general reduction in dopamine receptors. These changes can impair the function of brain areas rich in dopamine receptors, which might explain why individuals with drug dependence experience intense cravings or relapse, as their own dopamine production is no longer sufficient for normal stimulation. This reduction in dopamine transporters can contribute to problems with inhibitory control.

The brain also has opioid receptors, primarily mu (MORs), kappa (KORs), and delta (DORs). MORs are involved in motivational aspects, impulsivity, and the pleasurable effects of opioids. KORs, on the other hand, are part of an "anti-reward" system, mediating negative emotional states like depression and aversion, especially during opioid withdrawal. DORs are not as directly linked to drug reward but play roles in learning and memory, and can help alleviate negative moods. Chronic opioid use can decrease the body's natural pain-relieving chemicals (endorphins) and reduce the number or function of MORs, making individuals more dependent on external opioids and increasing tolerance and addiction risk. Methamphetamine use can also affect opioid receptors; for example, some studies show it can reduce the expression of MORs. The interaction between dopamine and opioid systems is significant, as dopamine receptor activation can influence MOR expression, particularly for stimulants like cocaine.

When multiple drugs are used together, the neurochemical effects can be different from using either drug alone. For example, combining methamphetamine and morphine can lead to stronger rewarding effects and higher dopamine levels in the nucleus accumbens compared to using either drug individually, increasing the potential for addiction. The combination can also produce different effects on dopamine turnover in the brain, which is linked to how the brain processes dopamine. Studies suggest that interactions between MORs and DORs can influence the reinforcing effects of polydrug combinations like heroin and cocaine. The effects of dopamine receptors, such as D1 and D2, also play different roles, with D1 receptors often enhancing self-administration of single drugs, while D2 receptors might inhibit the reinforcing effects of heroin when used with other substances.

Pharmacotherapy for Opioid Use Disorder and Methamphetamine Use Disorder

For Opioid Use Disorder (OUD), two primary medication treatments are methadone maintenance therapy (MMT) and buprenorphine, often combined with naloxone to prevent misuse. MMT, typically taken orally, has been shown to improve quality of life and reduce the spread of blood-borne diseases among opioid-dependent patients. However, there are concerns about its safety, especially for patients with other health conditions or those taking other medications, which can lead to negative drug interactions or worsen behavioral symptoms. Buprenorphine, a partial opioid agonist, helps maintain abstinence and keeps patients in treatment, often administered in specific dosages for maintenance.

Treating OUD becomes more complex when patients also use methamphetamine. Some studies indicate that methamphetamine use is common among OUD patients seeking treatment and can be associated with a higher risk of not continuing buprenorphine therapy. However, other research has found no clear link between methamphetamine use and outcomes for patients on methadone. Patients who use both drugs sometimes describe a "balancing effect," which can reduce their perceived need for OUD medications. For fentanyl abuse, a newer approach called micro-dosing buprenorphine, which involves starting with very small, increasing doses, has shown promise in preventing withdrawal symptoms during treatment initiation.

Psychosocial interventions are also a vital part of comprehensive treatment for opioid addiction and are often used alongside medication. These include Contingency Management (CM), which offers rewards for desired behaviors like abstinence, and Cognitive Behavioral Therapy (CBT), which helps patients identify and change problematic thoughts and behaviors. Studies show that patients receiving these therapies, especially when combined with medication, tend to attend more treatment sessions, achieve longer periods of abstinence, and show improvements in their psychological well-being. Other supportive therapies include motivational interviewing and web-based interventions.

For Methamphetamine Use Disorder (MUD), finding effective medical treatments has been challenging. Some studies suggest that buprenorphine may be more effective than other drugs like bupropion in reducing methamphetamine cravings. N-acetyl cysteine (NAC) has shown some potential in early studies for reducing cravings, but combining it with naltrexone might not offer additional benefits. Modafinil, another medication, has had mixed results in reducing methamphetamine use.

However, a sustained-release form of methylphenidate, a dopamine reuptake inhibitor, has been found to be safe and well-tolerated among active methamphetamine users. It significantly reduced methamphetamine use, cravings, and depressive symptoms. Similar to OUD, psychosocial interventions are highly effective for MUD. Cognitive Behavioral Therapy (CBT) can reduce methamphetamine dependence and improve patients' psychological health. The Matrix Model, a comprehensive treatment combining elements of CBT, motivational interviewing, and group therapy, has also shown greater success in increasing methamphetamine abstinence compared to standard care.

For polysubstance use, tailored treatments are being explored. Naltrexone implants, which slowly release the medication over weeks, have shown promise in helping patients stay in treatment and reduce the use of both heroin and methamphetamine. Combining buprenorphine and naltrexone has also been reported to reduce relapse in animal studies involving combined cocaine and morphine use. High doses of methadone have been found to reduce drug-seeking behaviors in individuals using both heroin and cocaine. Research also suggests that cooling interventions in the first 30 to 90 minutes after co-administering methamphetamine and morphine can reduce severe toxicity and lethality, highlighting a critical window for intervention.

Conclusion

The widespread occurrence and risks associated with using multiple drugs pose a significant threat to public health resources globally. Therefore, it is crucial to deepen our understanding of how individual drugs and their combinations affect the brain's chemical systems and overall behavior. This knowledge, particularly regarding polydrug combinations, is currently limited but essential for understanding their unique potential for addiction and their role in developing addictive behaviors. Future preclinical research that investigates the underlying causes and potential treatments for both single drug and combined morphine and methamphetamine abuse is very important. Given the complex nature of addiction and the powerful factors involved, understanding the mechanisms behind polydrug abuse and its link to addiction is critical for developing more effective treatments to address this ongoing public health crisis.

Introduction

Problems with drugs and alcohol are a serious concern around the world. These issues affect society, the economy, and people's health. The number of people using drugs like methamphetamine and opioids has grown very fast, even with many strong laws against drug use.

Recent reports show a big increase in hospital visits and deaths related to methamphetamine and other stimulants. These deaths are now more common than deaths from pain pills. Opioid overdoses and related deaths have also gone up. It is concerning that nearly half of deaths from stimulant use also involve opioids, and more opioid deaths are also linked to methamphetamine use. This shows that many people are using more than one drug.

Helping people who use drugs costs a lot of money worldwide each year. But this cost only covers a small number of users. If everyone who needed help got it, the cost would be much higher. Studies show that not treating drug use costs far more than paying for treatment. In the United States, drug-related healthcare costs include many things, like staying in a hospital for treatment, emergency medical help, and research to prevent and treat drug use.

Right now, one of the most studied treatments is for opioid addiction. Methadone treatment has been used to help with opioid addiction by reducing harm. Some reports say it helps lower risky actions. However, some people argue that for long-term treatment, methadone might not make life much better for patients. Methadone treatment also often means a lifelong commitment.

Other medicines, like buprenorphine, are mostly used in private settings because they cost a lot for ongoing treatment. Buprenorphine acts like an opioid, while naloxone blocks opioids and is often given as a shot to stop opioid overdoses. In some places, people have illegally injected buprenorphine mixes, which has led to more opioid addiction. Taking naltrexone by mouth for opioid addiction often does not work well because people don't stick with the treatment. However, naltrexone implants placed under the skin have shown some good results for treating opioid or multi-drug use. But how well these implants work in the long run, and the risk of overdose, have not been studied enough.

For methamphetamine addiction, there are no clearly strong drug treatments yet. Studies have shown some good results with certain drugs, while others, like antidepressants, did not work as well. Some studies have found that certain medicines can help lower the strong urge to use methamphetamine, but others did not show this effect.

This document will talk about how morphine and methamphetamine affect the brain and behavior, both when used alone and together. It will also cover new drug treatments for using one drug or many drugs.

Opioid Use Disorder

Opioid problems often start when doctors give out too many pain pills, and cheap, easy-to-get opioids make the problem worse. After using opioids for a long time, people need more of the drug to get the same pain relief. When they use higher doses to get the effect, they can face serious side effects like feeling sick when stopping the drug or dangerously slow breathing. Most opioid use worldwide is found in North America. Reports show that many people in countries like the UK, US, Australia, Germany, and France have misused prescribed pain pills.

Heroin, fentanyl, and morphine are common opioids used. Globally, around 115,000 people have died from opioid overdoses. The COVID-19 pandemic has made this death rate even worse. When someone is addicted to morphine, their body gets used to it, meaning they need more and more to feel its effects. This can lead to strong dependence because stopping causes severe withdrawal symptoms like stomach pain, nausea, diarrhea, watery eyes, and goosebumps.

When people stop using morphine after being dependent, they can feel bad emotions like worry, agitation, and unhappiness. Mental dependence means a strong urge for the drug, either to stop feeling sick or to get the good feeling it gives. Withdrawal symptoms make people crave the drug and lose control, making it hard to avoid using again. People with opioid addiction may also act without thinking and have trouble planning. They might also feel less joy from everyday things. These withdrawal symptoms are a main reason people keep using drugs and find it hard to stop.

Animal studies show similar effects to humans. For example, mice given opioids show signs of sadness and anxiety during withdrawal. They may move less or avoid other animals. They also show impulsive behavior, like acting without thinking or making quick, bad choices. Opioid use can also cause problems with learning and remembering.

Fentanyl use has caused many deaths in Europe and the US. It is a very strong opioid, much stronger than heroin or morphine. People often add fentanyl to heroin to make it stronger and more appealing, partly because it's cheaper. Fentanyl can cause sleepiness, slow breathing, and good feelings (though less than heroin or morphine). When stopping, it can cause withdrawal signs like diarrhea, stomach cramps, and bone pain. Studies on rats show that fentanyl use can change the brain's defense system and make brain thinking problems worse.

Methamphetamine Use Disorder

Methamphetamine, or meth, is a powerful drug that speeds up the brain. While it's sometimes used as a medicine for ADHD and weight problems, it's mostly misused for fun. Meth use, especially in its crystal form, is a big health problem, rapidly growing in Asia and North America.

Long-term meth use is linked to feeling tired, trouble sleeping, sadness, restlessness, more hunger, depression, and worry when people stop using it. Worry and sadness are very clear and bad when people first stop. Using meth for longer is linked to a higher chance of depression, worry, and seeing or hearing things that aren't real. Some problems, like craving and trouble sleeping, can last for up to a month after stopping.

People who use meth may also act without thinking when they stop, which can make them keep using the drug. Studies show that meth addiction greatly harms self-control and decision-making, showing problems with how the brain handles rewards. Meth use also affects thinking skills like remembering what was seen, how fast one can think and learn, short-term memory, and planning. Even stopping for a month might not fix these thinking problems, suggesting it takes longer to undo the damage from long-term meth use.

Animal studies also show that stopping meth use can lead to anxiety and sadness. The effects can vary based on the type of animal, how the meth was given, how much, and for how long. For example, some studies show changes in how much animals move, while others do not.

Co-Abuse of Opioid and Methamphetamine

Using many drugs together is a big health problem worldwide, especially among teens and young adults. Common drug mixes include cigarettes, alcohol, and marijuana. In the US, the use of opioids and methamphetamine is higher among people aged 18-49. Methamphetamine use has greatly increased among people seeking help for opioid addiction. In Malaysia, there has been a huge jump in people using many drugs at once. Also, in the US, nearly half of deaths linked to stimulant use involve opioids, and many opioid-related deaths also involve meth. This means people often use meth and opioids together.

Using more than one drug at once means people combine the effects of different drugs, either at the same time or separately. A common mix is stimulants and opioids, like "speedball" (opioids and cocaine) or "goofball" (opioids and methamphetamine). People with opioid addiction often use meth too, either separately or by injecting them together. They do this to balance the drug effects, get a stronger high, or lower the risk of overdose or withdrawal. People taking medicine for opioid addiction might use meth to get a different high or to reduce the sleepy effects of their medicine.

Using drugs one after another is also common. This means taking a drug after the main effect of another has worn off, often to ease withdrawal or keep a good feeling going. This includes using drugs that speed you up and drugs that slow you down, mainly to make withdrawal symptoms better. Sometimes, people use drugs of the same type to lessen the drug's effects or to make a high last longer, which helps manage their opposite mental effects. People who use meth along with other drugs are more likely to feel worried when they first stop. Studies also link using many drugs to worry and sadness. In some cases, how bad mental health problems are in people who use stimulants might be more linked to their opioid use than their stimulant use. Also, people who use meth and morphine together can have more extreme speeding up of breathing, heart, and nerves, and worse mental health problems than using either drug alone.

Although animal studies try to understand using many drugs, there's not enough proof to fully understand how it affects behavior and brain chemicals. However, some studies show that using morphine and meth together can lead to more extreme behaviors, like trying to escape, which suggests worry and stress from withdrawal. The withdrawal signs from using both drugs can be different from using either drug alone. Often, using drugs together can hide the bad effects of one drug. For example, a stimulant can hide the sleepy effects of morphine while making the opioid system more sensitive. Using meth and morphine together can also lead to stronger combined effects. This shows that the urge to use drugs is stronger when they are taken together.

Neurological Changes in Drug Dependent Brains

In 1950, health experts said that drug addiction is mostly about a mental need for the drug, no matter what drug it is. Early ideas linked addiction to needing more of the drug (tolerance) and feeling very sick when stopping (withdrawal), which was thought to be the main reason people couldn't quit. Later, scientists found that a brain system called the dopamine system was likely causing the good feelings from opioids and stimulants. These discoveries led to ideas that addiction has shared brain and mind reasons across different types of drugs.

When healthy people who don't normally use opioids take morphine once, it causes positive changes in brain areas linked to reward. But for people with long-term opioid addiction, stopping use can lead to fewer connections in some brain areas. Also, how bad their drug use was and their withdrawal signs were linked to how their brain reacted to things that reminded them of drugs. The brain and behavior changes seen in people who stop opioids also depend on how long they've stopped. For example, people who recently stopped felt less pleasure from normal good things and reacted more strongly to drug reminders, showing that brain areas linked to reward and stress change during the time a person stops using drugs.

Heroin is strongly linked to acting without thinking and bad choices because it harms brain areas needed for thinking. Brain scans show big changes and damage to brain connections (white matter) in heroin users, leading to different ways brain areas work together for reward, drive, memory, learning, and control—all important in addiction. These brain changes lower self-control, make it harder to stop bad actions, and make it difficult to handle stress. This harm to self-control shows up as more impulsive behavior in specific tests.

Fentanyl also affects the brain. Taking fentanyl once can lower a certain brain chemical by a lot. But using smaller amounts for a short time, or after people stopped using it for 2 weeks, showed no big changes in that brain chemical. This shows fentanyl affects brain chemicals differently depending on how long it's used. In animals, giving themselves fentanyl led to fewer connections in brain areas for movement, thinking, and senses, while connections in a reward area increased, similar to other opioids that lead to addiction. Long-term fentanyl use can also cause thinking problems, like sudden memory loss, with brain scans showing damage to memory parts of the brain.

One of the most common brain changes linked to methamphetamine is thinking skills getting worse. This affects brain areas important for self-control and making choices. Long-term meth use also causes a big loss of brain tissue (gray matter) in areas linked to emotions and memory, and a smaller memory part of the brain. These brain changes are linked to thinking problems. While some studies show that thinking skills can get much better after stopping meth for over 6 months, or even a year, others show that even after stopping for a month or longer, people who used meth might still have worse thinking skills than those who don't. This suggests it takes a long time to fix the thinking problems caused by long-term meth use. Teen brains are more easily harmed by meth, especially in a key brain network called the frontostriatal system. Stopping long-term stimulant use also changes how the brain works, shifting activity from outer brain layers to deeper parts. Psychosis (seeing or hearing things that aren't real) linked to meth addiction has been reported with changes in activity in specific brain areas.

Neurochemical Changes in Drug Dependent Brains

The dopamine system sends signals to brain areas linked to addiction, such as the striatum, hippocampus, and prefrontal cortex. Different parts of the dopamine system (D1 and D2 receptors) cause different reactions to rewards, bad things, and guessing future rewards or punishments.

When people or animals who don't normally use opioids take them once, it causes more dopamine to be released in the brain, which makes the drug feel good. But using opioids for a long time lowers dopamine release in the brain because the dopamine system changes. This low dopamine state is linked to not feeling enough reward, meaning people don't feel satisfied. However, some studies have different results. Sometimes, lower dopamine might make the body try to make more dopamine receptors.

Stimulants cause more dopamine release in the brain than opioids do, when taken once. This is because stimulants directly affect how dopamine moves in the brain. Overall, there's a drop in dopamine receptors when using stimulants. How meth affects dopamine depends on the dose; it blocks dopamine movement at low doses and reverses it at high doses. These changes cause problems in how brain areas rich in dopamine receptors work, which might be why people who are addicted crave drugs or start using again – their body's own dopamine isn't enough to feel good anymore. The loss of dopamine receptors may be due to damage to dopamine brain cells caused by meth. Long-term meth use lowers the amount of dopamine that can move in the brain, which is thought to be why self-control problems happen in addicted individuals. However, some studies report no such effects.

Opioid receptors have different types: mu (MORs), kappa (KORs), and delta (DORs). MORs control how people act, like their drive, acting without thinking, how they deal with bad things, and feelings of sadness. They easily connect with natural pain-relief chemicals and are mostly found in brain areas related to reward. KORs act like an "anti-reward" system, causing bad feelings like sadness, stress, unhappiness, and dislike, which are more noticeable when people stop opioids. MORs boost dopamine in one brain area, while KORs stop dopamine in others, leading to unhappiness. The initial good feelings, and later bad feelings, allow recreational drug use to turn into addiction.

Using morphine can increase MORs in some brain areas but lower them in others. Stopping long-term morphine use can also increase MOR activity in a brain area, which might be the body trying to adjust to changes during withdrawal. However, changes in MORs after long-term opioid use or withdrawal have shown different results in various studies, possibly due to differences in brain areas studied, how long drugs were used, the dose, and how they were given. Long-term use of opioids also lowers the body's own natural pain-relief chemicals and makes MORs less responsive. This makes people dependent on outside opioids because their body's own opioids don't work, leading to needing more of the drug and addiction. Unlike MORs and KORs, DORs are not linked to drug reward but more to learning and memory, and they can lessen bad moods. Long-term morphine use can lead to fewer DOR cells in the memory part of mouse brains, even after 4 weeks of stopping. This causes problems with memory, which is a common issue for people with opioid addiction when they first stop.

The brain adapts to meth use, with a lasting rise in MORs in one area, which happens at the same time as worry signs appear during withdrawal. However, MORs don't respond the same way to meth; their connections can change over time. Dopamine must be active for more MOR chemical instructions, showing how dopamine and opioid systems work together to cause the good feelings from stimulants. Also, MORs are important in controlling how the brain becomes more sensitive to meth's effects through dopamine signals. One study found that meth could relieve pain as much as morphine at certain doses. The pain-relieving effects of meth were stopped by a drug that blocks opioids, suggesting that MORs and meth work together at higher doses.

Using meth and morphine together can change the brain and behavior differently than using either drug alone. Studies have reported greater rewarding effects when morphine and meth are used together compared to using each drug alone. Small amounts of both drugs given together caused animals to prefer the drug place more and for longer. This matches human studies where small amounts of morphine and meth led to a strong urge to use more. Regularly using small amounts of both drugs also raised dopamine levels in one brain area more than using either drug alone, showing stronger effects when taken together.

A dose of both drugs together can make dopamine levels in one brain area much higher than either drug alone, but it can slow down how fast dopamine is used. This shows that the drug combination has different effects on dopamine signals in the brain than either drug alone. Different dopamine systems in the brain are affected differently by stimulants and opioids. The effects of small doses of cocaine are made stronger when a small amount of heroin is added, causing more dopamine to be released in a specific brain area. This likely happens through MORs and DORs in that brain area. Also, D1 and D2 dopamine receptors work differently when heroin and cocaine are used together. D1 receptors make people want to use heroin or cocaine more, while D2 receptors stop the urge to use heroin when both are taken.

Pharmacotherapy for Opioid Use Disorder and Methamphetamine Use Disorder

For opioid addiction, methadone doses vary. People taking methadone by mouth for over 3 months showed a better quality of life and lower rates of blood-borne diseases. However, there are concerns about the safety of methadone treatment, especially for patients who also take other prescribed drugs, as this can lead to unwanted drug interactions or worsen mental health problems. Methadone can also have side effects on the kidneys and heart. Buprenorphine is another medicine that helps people stop opioid use, delays starting again, and keeps them in treatment. To prevent misuse, buprenorphine is often given with naloxone.

Methamphetamine use is common among opioid users seeking treatment. Some studies show meth use is linked to people stopping buprenorphine treatment, while others found no link between meth use and staying off opioids during methadone treatment. Patients have said that using both drugs helps them function better, which might make them feel they don't need their opioid addiction medicine as much, leading them to stop treatment.

For fentanyl addiction, a study found that most patients on methadone treatment stayed off fentanyl for 6 months, but many still went back to using it. Some people use illegal buprenorphine to treat themselves for fentanyl addiction, but some found that illegal fentanyl still caused unexpected withdrawal symptoms even when using buprenorphine. A method called "micro-dosing" buprenorphine (giving very small, increasing doses) is being looked at for fentanyl addiction, as it seems to cause very mild withdrawal.

Along with medicines, talking therapies like reward-based therapy (Contingency Management, CM) and Cognitive Behavioral Therapy (CBT) are approved for opioid addiction. Studies show that people who receive CM go to treatment more often and stay off drugs longer. CBT also helps people have a more positive outlook and fewer emotional outbursts. Other talking therapies include counseling about drug and HIV risks, motivational talks, and online therapies.

Methadone treatment is also prescribed for long-term methamphetamine users. Buprenorphine seems to be better than some other drugs at lowering methamphetamine cravings during withdrawal. A drug called N-acetyl cysteine (NAC) may help with meth addiction by stopping cravings, but it's not clear if people actually use less meth. When NAC was combined with naltrexone, it was no better than a fake pill at reducing meth cravings.

Modafinil, another drug, did not help lower meth use in some studies, but others found that people who took it as told were more likely to use less. Varenicline, taken twice daily, did not help people stop meth use or make treatment work better than a fake pill. However, a slow-release form of methylphenidate was safe for meth users and greatly lowered meth use, cravings, and sadness.

Talking therapy (CBT) has helped lower meth addiction and improved mental well-being for patients on methadone. CBT also reduced cravings for meth users with HIV/AIDS. Other talking therapies have shown to reduce meth use and mental health problems. The Matrix model, which combines many types of therapy, worked better at helping people stop meth use than just CBT alone. Combining motivational talks and CBT has also been found effective in helping people stop using meth.

Polysubstance use

Naltrexone implants placed under the skin for 12 weeks helped more people stay in treatment and use less heroin and meth, showing early proof of effective drug treatment for using many drugs. Also, a mix of buprenorphine and naltrexone helped stop animals from starting to use cocaine and morphine together again. For people using heroin and other drugs, reward-based therapy might help if they have already stopped using many drugs. But generally, the study did not show strong results, possibly because the people in the study continued to use illegal opioids a lot.

High doses of methadone have also helped reduce the urge to seek heroin and cocaine, possibly by making drug reminders less appealing. In studies, a drop in body temperature was seen after using meth and morphine together. Cooling helped after 30 minutes of using both drugs together. One study showed that the deadly effect of using meth and morphine together was largely stopped by cooling for 30 to 90 minutes. Normal actions returned as body temperature went back to normal. Both studies pointed to a "golden hour" for cooling to treat the harmful and deadly effects of using both drugs together.

Conclusion

The common and dangerous practice of using many drugs at once puts a strain on health resources around the world. So, it's very important to better understand how single drugs and drug mixes affect the brain's chemicals. This understanding is still limited, especially for drug combinations that can create unique addiction problems.

It's important to value new animal studies that look at how morphine and meth (alone and together) affect the body and how to treat these problems. Addiction is a very complex illness with many powerful parts. To find better and more effective treatments for this ongoing public health problem, we need to understand how using many drugs is linked to addiction.