The use of illicit stimulants such as methamphetamines and cocaine, and the misuse of prescription stimulants, have been a growing healthcare concern in the United States for many decades. Misuse of these substances can lead to development of a stimulant use disorder (StUD). A steady rise in availability and manufacturing of methamphetamines, along with increased cocaine use in adults and adolescent populations, continues to perpetuate this healthcare problem ^[1][2][1,2]. A study assessing the prevalence of stimulant use for medical purposes estimated a 79.8% increase in stimulant use from 2013 to 2018 [3].

While prescription stimulants have been proven to be an effective treatment option for Attention Deficit Hyperactive Disorder (ADHD), legitimate concerns have come with studies showing high levels of medical misuse, nonmedical use, and stimulant diversion [4]. The increased misuse of prescription stimulants was assessed in a short-term study which showed that the estimated number of emergency department visits involving ADHD prescription stimulants had steadily increased among those aged 18 years and older from 13,379 visits in 2005 to 31,244 visits in 2010 [5]. These epidemiological findings represent the growing threat of stimulant misuse, which demands action.

Behavioral therapy remains the only therapeutic option with proven efficacy for treating StUD. However, stimulants are often associated with high levels of relapse, and behavioral therapies are largely ineffective in the long term. While behavioral therapy can provide individuals with initial coping strategies, other treatment modalities should be utilized to prolong stimulant abstinence. Currently, evidence accessing various pharmacological treatments shows little to no significant efficacy in treating StUD. Neuromodulation is a new form of treatment that has been utilized in neurology and psychiatry and is continuously being studied for its efficacy as a future treatment for addiction-related disorders. One important neuromodulation technique known as transcranial magnetic stimulation (TMS) has provided evidence for decreased cravings among cocaine users.

1.1. Cocaine

Acute administration of cocaine has profound effects on neuronal activity and cerebral blood flow [6]. Cocaine binds to the monoamine transporters for dopamine, norepinephrine, and serotonin within the synaptic cleft. As a stimulant, these transporters’ binding inhibits the monoamines’ reuptake, which enhances post-synaptic activity [7]. The elevated level of dopamine then activates dopaminergic G-protein-coupled receptors (GPCRs) in the mesocorticolimbic dopamine pathway, which is responsible for the reinforcing properties of the drug [8]. The transcriptional regulator ∆FosB, which modulates AMPA glutamate receptor synthesis, is stimulated by D₁-receptors. ∆FosB elevates the glutamate receptor subunit GluR1 in the ventral tegmental area following discontinuation of cocaine and could lead to addiction [9]. However, it is important to recognize that cocaine affects organ system beyond the brain, including the cardiovascular system, and can lead to changes in cerebral blood flow, vasoconstriction, vasculitis, atherosclerosis, systolic and diastolic dysfunction, and arrhythmias [10].

1.2. Methamphetamine

Methamphetamine exhibits profound addictive stimulant properties and strong dysregulation of neural circuitry [11]. It readily passes through the blood–brain barrier (BBB) to provoke rapid and intense euphoria [12]. As a sympathomimetic, methamphetamine increases heart rate, blood pressure, body temperature, heightens alertness, and decreases appetite. Administration of amphetamines stimulates the release of the monoamines norepinephrine, serotonin, and dopamine, greatly enhancing their synaptic levels [13]. Euphoric effects of methamphetamine are attributed to the overstimulation of dopamine. Chronic administration of methamphetamine contributes to nerve terminal damage in the dopaminergic system leading to potential motor deficits such as: impaired motor function, cognitive decline, anxiety, depression, hallucinations, violent behaviors, and delusions ^[14][15][16][14,15,16]. Users often experience immediate effects such as methamphetamine-induced restlessness, insomnia, and irritability. Continued use of methamphetamine can render the user with unwanted side effects such as dyskinesia and other movement side effects. The acute withdrawal phase begins with symptoms lasting between seven and ten days, peaking around 24 h after the last use. Withdrawal symptoms include dysphoria, fatigue, vivid and unpleasant dreams, increased appetite, and psychomotor alterations. The severity of symptoms is use-dependent and often varies with age and dependence [17]. As with cocaine, methamphetamine affects many organ systems beyond the brain, notably the cardiovascular system ^[18][19][18,19].

2. Current Treatment of StUD

Current public health concerns regarding the increased use of stimulants in the United States present ongoing efforts to unveil new protocols for diagnosing and treating StUD. Unlike opioid use disorders, current treatment options for StUD are very limited and only include behavioral interventions with no known FDA-approved pharmacotherapies. Over the years, suggested pharmaceutical treatments have been used off-label but have not provided any statistical effectiveness among various studies. A multi-center study assessed the use of bupropion and injectable naltrexone, but the authors could not reach a definite conclusion that this medication combination was superior to the placebo [20]. Nevertheless, advances in neurobiology and neurotechnology have allowed researchers to better grasp the neuropathological basis of dependence associated with stimulant use ^[21][22][21,22]. These advances have provided a greater opportunity for the future development of pharmacological interventions which could be used in conjunction with known effective behavioral therapies [23].

2.1. Current Behavioral Interventions for StUD

Behavioral therapies have been influential in treating many forms of drug dependence. In treating StUD, behavioral interventions remain the only modality that has shown proven benefits through clinical studies. Four of these interventions include contingency management (CM), cognitive-behavioral therapy (CBT), community reinforcement approaches (CRA), and motivational interviewing (MI). The most effective behavioral intervention used to treat StUD currently is CM. This intervention has proven great efficacy in treating other substance use disorders, including alcohol, cannabis, nicotine, and opioids. During this intervention, material incentives are delivered to patients upon meeting expected goals for stimulant abstinence. This repeated reward stimulus trains the brain to reverse the desire for stimulant use. Individuals undergoing this treatment have displayed reduced psychological and physiological symptoms such as drug craving, mood/affect, and drug abstinence in patients diagnosed with StUD. In a systematic review and meta-analysis of 157 studies looking at treatment options for cocaine, CM programs, when compared to other psychotherapies, revealed provided the only significant likelihood that patients would provide a negative cocaine test [24]. Another study showed individuals receiving CM treatment compared to those who underwent psychosocial treatment for methamphetamine submitted more negative urine tests than those receiving standard care [25]. Additionally, this study provided evidence that CM procedures could be altered to allow for less frequent disbursements of reinforcements while still providing similar treatment efficacy. These studies are a few of many that point to CM as being a highly beneficial treatment option for StUD. Another common behavioral treatment option for individuals diagnosed with StUD is CBT [26]. This approach seeks to reduce behaviors and thoughts associated with stimulant use through applying techniques such as motivational enhancement, relapse prevention, and stress management, which further help the patient cope with various drug-seeking triggers. The treatment formats for CBT often include individual therapy, group therapy, and, more recently, computer-based therapy. CBT has been extensively used for methamphetamine, though evidence of its effectiveness is still scarce. In a recent study, evidence for the use of CBT as a treatment for methamphetamine misuse was low and provided inconclusive findings as to the effectiveness or ineffectiveness of CBT [27]. The lack of evidence requires more research to address the effectiveness of CBT. While some behavioral interventions have proven to be successful in treating individuals with StUD, it is necessary to find other treatment options that are more universally accessible and provide decreased relapse and better retention rates. Future studies should focus on the efficacy of using various behavioral treatment options in conjunction with other treatment modalities.

2.2. Pharmaceutical Interventions Being Studied

Much of the current research regarding StUD treatments involves potential pharmaceutical therapies targeting neurochemistry to reduce dependence and promote abstinence from stimulants. Some pharmacological agents being tested aim to reduce symptoms associated with StUD of a methamphetamine or amphetamine subtype. These medications include gabapentin, mirtazapine, bupropion, and rivastigmine, among others. Some of these drugs have effectively decreased psychiatric issues, which often provoke addictive behavior. However, these treatments have thus far failed to show consistent evidence of effectiveness between studies. Mirtazapine is currently FDA approved as an atypical antidepressant that is being studied as a potential treatment option for AMD by reducing stimulant craving. This drug option acts on the mesocorticolimbic system of the brain by inhibiting alpha-2-adrenergic receptors causing an increased release of norepinephrine, serotonin, and dopamine [28]. In a placebo-controlled experiment among cis-gender men and transgender women, mirtazapine treatment and counseling provided reductions in positive urine tests at 24 and 36 weeks of treatment ^[29][29]. Furthermore, comparing this study with others in a systematic review display similar findings with treatment groups showing small changes in methamphetamine use compared to placebo [14]. More robust studies looking at larger populations should be performed to render a conclusion about the effectiveness of mirtazapine [30]. Furthermore, pharmacotherapies for treating cocaine use disorders (CUD) show similar results with little effectiveness among many common drug classes [31]. Of the many studied pharmacotherapies, topiramate seems to be potentially effective in presenting abstinence. This could be achieved by the capacity of topiramate to facilitate GABAergic neurotransmission while inhibiting glutamatergic activity, which has been speculated to reduce the rewarding properties of cocaine and reduce craving [32]. Further studies should also evaluate these medications in conjunction with behavioral interventions.