Therapeutic Applications of Amphetamine-like Psychostimulants: Comparison
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Amphetamine-type stimulants such as lisdexamphetamine dimesylate, mixed amphetamine salts, 3,4-methylenedioxymethamphetamine (MDMA), dextroamphetamine, and phentermine have been investigated for their potential in treating a range of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), drug dependence, post-traumatic stress disorder (PTSD), and obesity. Lisdexamphetamine dimesylate has shown promise in effectively treating ADHD symptoms in both children and adults. Additionally, it has been explored as a potential treatment for drug dependency and withdrawal, demonstrating encouraging results. Mixed amphetamine salts have also exhibited efficacy in reducing ADHD symptoms in adults.

  • amphetamines
  • stimulants
  • therapeutic

1. Introduction

Nowadays, psychotherapies are promoted as effective and cost-efficient treatments for a range of psychiatric disorders. Global awareness of psychiatric disorders has increased, with these disorders being associated with significant disease burdens and high rates of morbidity and mortality [1]. They often co-occur on a large scale with additional healthcare issues, aggravating the overall medical symptoms and complicating the management of medical conditions. As a consequence, there is a greater emphasis on the need for evidence-based pharmaceutical and psychotherapy treatments for psychiatric illnesses [2]. Pharmacotherapy is a type of psychotherapy that involves the use of medication in cases of substance misuse or addiction. It usually entails the use of typically abused drugs to aid therapy processes and promote recovery [3]. The administration of illicit drugs in therapy is an intricate and controversial issue. While most abused drugs present harmful effects, alongside being illegal, some of their compounds have shown potential therapeutic benefits when administered under controlled conditions [4].
Several drugs of abuse have been investigated for therapeutic purposes and shown to lead to significant and lasting positive changes in the overall status of patients. Psychedelic substances such as 3,4-methylenedioxyethylmethamphetamine (MDMA), psilocybin [5], and lysergic acid diethylamide (LSD) [6] have been studied in conjunction with therapy for various mental health conditions due to their properties [5,6][5][6]. MDMA is a stimulant and empathogen with the potential to treat post-traumatic stress disorder (PTSD), with its use involving limited administrations [7,8][7][8]. Psilocybin, a natural psychedelic compound found in certain species of mushrooms, has been investigated for its potential in the treatment of mental health conditions related to anxiety, depression, cancer, and substance use disorders [9,10][9][10]. Likewise, several studies have explored LSD’s therapeutic benefits for substance use disorders, PTSD, anxiety, and depression. These benefits include long-lasting mood improvements, symptom reduction, and increased well-being [6]. Dissociative anesthetics, such as ketamine, have also been studied and used to treat conditions such as suicidal ideation and severe depression [11]. This substance has shown rapid antidepressant effects, particularly in individuals who have not responded to other treatments [12].
Cannabis, a well-known recreative drug, has been legalized for medical use in several jurisdictions, being prescribed to alleviate symptoms associated with chronic pain, terminal cancer, nausea induced by chemotherapy, multiple sclerosis, and epilepsy [13]. Medical cannabis typically contains low levels of tetrahydrocannabinol (THC) and high levels of cannabidiol (CBD). THC is the psychoactive compound associated with the recreational use of marijuana [14].
Opioids have also been included in several clinical trials. In the treatment of opioid addiction, Methadone, a long-acting opioid agonist, is often combined with buprenorphine, a partial opioid agonist [15], or naltrexone, an opioid antagonist [16,17][16][17]. These medications help relieve withdrawal symptoms and reduce drug and alcohol cravings. Buprenorphine, in particular, reduces the risk of respiratory depression and overdose due to its ceiling effect, allowing individuals to stabilize their lives and engage in other aspects of treatment [15]. Naltrexone, on the other hand, neutralizes the pleasurable effects of opioids in the brain. Low-dose naltrexone has gained popularity due to its efficacy in managing chronic pain conditions [16,17][16][17]. It is critical to note that the therapeutic use of these substances requires the careful consideration of their potential risks and benefits [4]. Thoughtful deliberation, qualified guidance, and conformity to legal and ethical norms are mandatory prerequisites, especially since the toxicity mechanisms of all these drugs have not yet been fully established [18]. The substances’ characteristics, duration of treatment, and respective dosages need to be adjusted to the individual’s specific needs and continuously monitored by a qualified medical professional [4].
This subject is rapidly attracting interest, with ongoing research and debates about the safety, efficacy, and proper usage of chemical substances. It remains unknown how illicit drugs will be utilized in the near future, although novel responses, the clinical repurposing of old drugs, and the production of new compounds are inevitable outcomes. According to the United Nations Office on Drugs and Crime (UNODC), in 2019, approximately 27 million people worldwide were consuming amphetamines, with ages ranging between 15 and 64 years old [19]. Additionally, the 2021 report from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) estimates that 1.4 million young adults (15–34 years old) have already consumed amphetamines [20], making amphetamine Europe’s second most consumed stimulant after cocaine [19].

2. Lisdexamphetamine Dimesylate

Several studies have shown the safety and efficacy of using lisdexamphetamine dimesylate (LDX) in the treatment of several medical conditions. ADHD and drug dependency are examples of conditions wherein this compound has shown promising results in terms of recovery and therapeutic applications. Regarding ADHD, five articles published in the last 3 years have investigated the use of LDX to treat the symptoms related to this condition. Childress et al. [44,45,46][21][22][23] published three studies that highlighted the safety, tolerability, and efficacy of LDX in children aged 4–5 years [44,45,46][21][22][23]. All of the studies had a similar structure, encompassing screening and washout, dose optimization, dose maintenance, and a safety follow-up, with doses ranging from 10 to 30 mg LDX per participant [44,45,46][21][22][23]. Focusing on a different age range, Adler et al. [47][24] demonstrated that for concentrations between 30 and 70 mg a day, the used of LDX in adults with ADHD and Comorbid Sluggish Cognitive Tempo (SCT) was beneficial, showing significant improvements in SCT when compared to a placebo [47][24]. Wang et al. [48][25] adopted a different approach, studying striatal and thalamic functional connectivity (FC) using static (time-averaged) and dynamic (time-varying) measures to then correlate those results with ADHD symptom improvements after treatment with a long-acting LDX [48][25]. Despite limitations due to the small sample size and wide age range, the results support that the active treatment with LDX significantly improved ADHD-related symptoms [48][25]. The most frequently reported treatment-emergent adverse events (TEAEs) across the five studies were decreased appetite, insomnia, irritability, dry mouth, and headaches, all of which were considered to be mild to moderate in severity [44,45,46,47,48][21][22][23][24][25].
LDX has also demonstrated a beneficial effect with respect to treating illicit drug dependency and withdrawal. Since there is no medication approved for methamphetamine use and withdrawal, LDX has the potential to be used as an agonist for therapy aimed at ameliorating withdrawal symptoms [49][26]. Acheson et al. [50][27] used a tampered amount of LDX to study the feasibility and safety of its use in treating acute methamphetamine withdrawal [50][27]. The regimen started at 250 mg daily, with a 50 mg reduction per day until reaching 50 mg on day 5, and the results demonstrated that the regimen applied was a safe and feasible treatment [50][27]. On the other hand, LDX has also been tested in methamphetamine-dependent adults, with doses similar to those of Acheson et al. [50][27] showing very promising results [51][28]. A reduction in methamphetamine usage and cravings was observed, while the treatment was also confirmed to be safe, with adverse events being reportedly mild to moderate in severity [51][28]. This use of LDX also applies to other drugs of abuse, such as cocaine. Mariani et al. [52][29] tested this application in the context of cocaine use disorder (CUD) to determine the safety, tolerability, and optimal dosing of LDX, reaching the conclusion that an application of approximately 140 mg is safe and generally well tolerated, claiming it to be appropriate for future studies [52][29].
Due to the characteristics of amphetamines and LDX, it is only natural to explore their potential in the context of eating disorders/obesity cases. An interesting case report by Preddy et al. [53][30] relates the case of a young boy with Prader–Willi syndrome (PWS) who used LDX to manage weight loss and obesity [53][30]. PWS is associated with significant weight gain and obesity, and this symptom has been unsuccessfully controlled in patients for many years [53][30]. For this particular patient, LDX showed an immediate and significant reduction in appetite and consequent weight loss. A significant improvement in functional status and overall day to day living came as a result of this treatment, and the patient remained on LDX [53][30].

3. Mixed Amphetamine Salts

ADHD affects a great part of the world population, continuously prompting the testing and creation of treatment alternatives to LDX. Psychostimulants are commonly employed in ADHD treatment, and mixed amphetamine salts (MAS) are another type of amphetamine derivatives that have shown promising results when used for this purpose. Fick et al. [54][31] and Adler et al. [55][32] tested the long term safety and efficacy of a triple-bead mixed amphetamine salt in adults with ages ranging from 18 to 55 years [54,55][31][32]. Fick et al. [54][31] observed that doses of 25–75 mg of MAS significantly reduced ADHD symptoms in adults, although no dose–response efficacy was statistically proven [54][31]. Long term safety was assessed by Adler et al. [55][32] in a 12-month exposure study that confirmed the safety and efficacy of MAS, with the most commonly reported TEAEs being similar to that of LDX (insomnia, headache, dry mouth, upper respiratory tract infection, decreased appetite, weight decreased, and nasopharyngitis [55][32]).
Each patient is different, and each treatment with MAS may induce different results and TEAEs. Sedation and lethargy are extremely rare adverse effects that may appear with the administration of psychostimulants, and it has been shown that MAS are no exception [56][33]. Thus, it is of extreme importance for clinicians to always follow up on MAS administration and therapy, especially when it comes to treating ADHD symptoms in patients on the autism spectrum [56][33].
ADHD can be accompanied by other conditions, such as bipolar disorder (BD) or symptoms indicative of both disorders occurring simultaneously [57][34]. Existing findings suggest that psychostimulants can effectively and safely manage the manic symptoms of BD when used without a mood stabilizer. However, these medications carry an elevated risk of inducing psychotic and manic symptoms, especially in the absence of a mood stabilizer [57][34]. Further research into the use of MAS for treating BD without relying on mood stabilizers should be undertaken while remaining mindful of the potential risks associated with BD and its associated psychotic and manic symptoms [57][34].
CUD remains a significant public health issue, and amphetamines are among the few medications showing promising therapeutic results [58][35]. Impairments in dopamine transmission predict non-responsiveness to behavioral therapy, underscoring the potential significance of drugs like MAS, which have substantial control over the dopaminergic system. However, a number of medical, psychosocial, and practical factors, such as the possibility of abuse or diversion, health issues like cardiovascular disease, the worsening of psychiatric conditions like BD or anxiety disorders, and insurance coverage of off-label psychostimulants, make it difficult to treat cocaine or other stimulant use disorders with psychostimulants [58][35].
Combining MAS with topiramate has yielded promising results, indicating that individuals with cocaine dependence (those who consume cocaine at least nine times per month) have a higher likelihood of achieving abstinence when treated with a combination therapy involving extended-release MAS and topiramate compared to those receiving a placebo [59][36].

4. 3,4-Methylenedioxymethamphetamine (MDMA)

Studies have demonstrated that, when used in conjunction with psychotherapy, MDMA is effective in significantly reducing the clinical symptoms associated with PTSD [60][37]. However, this treatment has not been extensively studied in relation to posttraumatic growth (PTG), which encompasses positive transformations in self-perception, interpersonal relationships, or overall life philosophy [60][37]. To address this, Gorman et al. [60][37] evaluated the effects of MDMA-assisted psychotherapy on PTG and PTSD, demonstrating more significant reductions in the severity of PTSD symptoms compared to the placebo group. Importantly, these improvements were sustained, both immediately after treatment and at the 12-month follow-up. The findings of Jerome et al. [61][38] further support the potential of MDMA-assisted psychotherapy, indicating that this approach, involving two to three sessions with proper preparation and follow-up, holds promise for maintaining clinically significant improvements in PTSD symptoms for at least 1 to 3.8 years following treatment.
In a multi-site phase 3 clinical trial, Mitchell et al. [62][39] employed a randomized, double-blind, placebo-controlled approach to investigate the effectiveness and safety of MDMA-assisted therapy for individuals with severe PTSD. The study included participants with common comorbidities, such as dissociation, depression, a history of alcohol and substance abuse, and childhood trauma. Their findings reveal that MDMA-assisted therapy exhibits remarkable efficacy in treating severe PTSD and that it was well tolerated and safe, even for individuals with comorbid conditions [62][39]. Moreover, MDMA-assisted therapy for severe PTSD has the potential to result in subclinical improvements in alcohol use. Importantly, there was no evidence to suggest that MDMA increased the risk of illicit drug use [63][40]. Similar positive results were obtained concerning sleep regulation and fear conditioning and extinction [64,65][41][42]. The most frequent adverse events observed were elevated blood pressure, headache, anxiety, and tachycardia, but all reported adverse events were of mild to moderate severity, temporary in nature, and did not necessitate medication or intervention. In other words, no serious adverse events were observed [65][42].
Initial evidence suggesting that MDMA-assisted psychotherapy has the potential to be a safe and viable treatment for individuals with life-threatening illnesses (LTIs) in terms of reducing anxiety and alleviating other associated psychiatric symptoms has also been supported by Wolfson et al. [66][43]. The results of their study support the feasibility of utilizing MDMA-assisted psychotherapy as an innovative approach for the long-term management of anxiety related to LTIs [66][43].

5. Amphetamine, Phentermine, Dexamphetamine, and Dextroamphetamine

In a study conducted by Faraone et al. [67][44], the treatment effect size of amphetamine extended-release oral suspension (EROS) was assessed at various time points throughout the day (1, 2, 4, 6, 8, 10, 12, and 13 h post-dose). The findings indicated that amphetamine EROS demonstrated a strong and consistent effect in treating ADHD symptoms in children aged 6–12 years. Beneficial effects were observed to start early in the morning and persist throughout the entire day.
Swerdlow et al. [68][45] examined the effects of amphetamine on auditory frequency modulation learning (auditory learning) in targeted cognitive training for schizophrenia [68][45]. Amphetamine doses of 2.5–5 mg showed significant improvements in auditory learning, with maximal effects observed at 5 mg. These effects were consistent at 60 and 210 min after administration.
Cutler et al. [69][46] investigated the efficacy of dextroamphetamine transdermal system (d-ATS) as an alternative to oral formulations for ADHD treatment [69][46]. d-ATS proved effective in treating ADHD in children and adolescents, showing significant improvements and a large effect size and number needed to treat (NNT) of 2–3 for a clinically meaningful response [69][46]. The treatment demonstrated good tolerability, with minimal reports of dermal reactions and a low incidence of TEAEs overall [69][46].
Similar to MAS, dexamphetamine has displayed promising results in the treatment of cocaine dependence [70][47]. In a study by Blanken et al. [70][47], the efficacy of sustained-release dexamphetamine was demonstrated in reducing cocaine use among patients with cocaine dependence. This treatment not only led to decreased cocaine use but also showed potential for improving health-related outcomes in individuals with co-occurring heroin dependence who were undergoing heroin-assisted treatment [70][47]. In a case report by Palis et al. [71][48], dextroamphetamine was prescribed to a 51-year-old male with concurrent opioid and stimulant use disorder undergoing injectable opioid agonist treatment, resulting in a significant reduction in cocaine use [71][48].
Phentermine has been found to be an effective short-term treatment for obesity, according to research conducted by Márquez-Cruz et al. [72][49]. Their study revealed that the 30 mg dosage of phentermine was more effective than the 15 mg dosage after a 12-week follow-up, although there was no significant difference at the 24-week mark. Both long-term doses of phentermine were well tolerated and considered safe. Approximately 80% of the subjects experienced positive outcomes after continuing to use phentermine for an additional three months. In a study conducted by Pérez-Cruz et al. [73][50], the short-term administration of phentermine at a daily dose of 15 mg, combined with a lifestyle intervention program, resulted in a 19% reduction in hepatic steatosis and a greater loss of fat mass in kilograms among patients who were candidates for bariatric surgery. These findings suggest that phentermine could be a viable treatment option in preoperative interventions for individuals undergoing (or set to undergo) bariatric surgery.

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