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Oxytocin for Methamphetamine Use Disorder: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Amber Edinoff.

The treatment of substance abuse with oxytocin is a novel approach to a challenging public health issue that continues to contribute to a growing economic cost for societies worldwide. Methamphetamine addiction is one of the leading causes of mortality worldwide, and despite advances in understanding the neurobiology of methamphetamine addiction, treatment options are limited. The effects of oxytocin on methamphetamine use outlined should act as a catalyst for further investigation into the efficacy of treating stimulant use disorder, methamphetamine type with oxytocin in humans. 

  • oxytocin
  • treatment
  • methamphetamine

1. Introduction

The treatment of substance misuse with oxytocin is a novel approach to a challenging public health issue that continues to contribute to a growing economic cost for societies worldwide. Methamphetamine is a common drug of abuse and contributes to many detrimental health outcomes [1]. Drug addiction is one of the leading causes of mortality worldwide, and despite advances in understanding the neurobiology of drug addiction, treatment options are severely limited [2]. Current therapies for stimulant use disorder include antidepressant, anxiolytic, and mild stimulatory pharmacologic agents, though none are FDA approved. Additionally, alternative therapies such as behavioral and herbal remedies have led to limited therapeutic results and have been widely ineffective in clinical use [3].
Although there are currently many different treatments for substance abuse and, more specifically, methamphetamine use disorder, which remains to be a challenging disease to treat. For example, many cocaine rehabilitation programs have dropout rates of up to 50% due to the lack of effective pharmacotherapies that adequately treat withdrawal symptoms [3]. Due to the shortcomings of these attempts to treat a complicated psychiatric disorder, recent attention to oxytocin therapy (OT) has gained momentum in clinical studies as a possible therapy in the context of social stress, social anxiety, social cognition, and psychosis [4,5][4][5].
Endogenous oxytocin is a nine amino acid peptide that is produced by the hypothalamus and enters the peripheral circulation [6]. Peripherally, oxytocin promotes uterine contraction and lactation, during the intrapartum and postpartum period but additional receptors are located in the kidneys, pancreas, and heart. Furthermore, central oxytocin receptors have been located in the mesocorticolimbic system and other nuclei in the brain, including the medial and central amygdala (CeA), substantia nigra (SN), paraventricular thalamic nucleus, olfactory nucleus, hippocampus, brainstem, and the spinal cord, among others [6,7][6][7]. Oxytocin can also produce enhanced connectivity between cortical regions [8]. Modifying central neurotransmitter function in these regions is understood to attenuate neurobehavioral manifestations, including bonding, maternal, and stress-reducing behaviors, and contributes to the sensation of reward, stress, social affiliation, learning, and processing memories.
Due to recent developments in the understanding of oxytocin neurophysiology, targeting the central neuromodulation of oxytocin may induce improved symptomatic effects in treating methamphetamine use disorder. Due to the current advancements in oxytocin neurophysiology and modulation of behavior in the setting of chronic drug abuse, the medical community has brought further attention to oxytocin as a possible pharmacotherapy, which warrants further clinical investigations [7].

2. Methamphetamine

2.1. Epidemiology

The use of methamphetamine, a highly addictive psychostimulant, continues to grow with devastating effects throughout the United States and worldwide. The use of the drug soared in the 1990s, mainly in the midwestern and western parts of the USA, eventually reaching epidemic status in the early 2000s [9]. In an attempt to temper the use and production of methamphetamine, many state governments began limiting over-the-counter access to methamphetamine precursor products such as pseudoephedrine in 2004 [10]. The federal government followed closely behind with federal legislation to impose the same limits in 2006 [10]. These regulations did cause methamphetamine use and laboratory incidents to trend downward for a few years; unfortunately, the 12-month prevalence of methamphetamine use by persons 12 years and older increased by 195% from 2010 to 2018 in the USA [11]. The prevalence of methamphetamine use, in 2019, was 0.7% which showed no significant increase from 2018. Recent data from the National Survey on Drug Use and Health (NSDUH) regarding methamphetamine use in the USA concluded that the number of people with stimulant use disorder methamphetamine type was 1,048,000 in 2019 [12]. This is a significant increase as compared with the data from 2016, which showed 684,000 people with stimulant use disorder methamphetamine type [12]. Two million people 12 years or older reported using the drug in the past year [12]. Overall, methamphetamine has a strong presence throughout the United States, which indicates that this psychostimulant will continue to be a significant component of the drug epidemic for years to come.

2.2. Pathophysiology

Methamphetamine works through various mechanisms to increase the availability of catecholamine neurotransmitters, including dopamine and norepinephrine, in nerve terminals in the central nervous system (CNS) and peripheral nervous system (PNS) [13]. Amphetamines, including methamphetamine, act as substrates for the plasmalemma dopamine transporter (DAT), allowing admittance into dopaminergic pre-synaptic terminals [14,15][14][15]. After amphetamines are in the presynaptic terminal, they interact with vesicular monoamine transporter 2 (VMAT2) to trigger dopamine release into the cytosol, disrupting the pH balance [16]. Following the release, cytosolic dopamine concentrations remain high because amphetamines also interfere with the vesicular reuptake of the catecholamine via VMAT2 [17]. Catecholamines are metabolized by the mitochondrial enzyme monoamine oxidase (MAO); methamphetamine interferes with MAO function to inhibit the metabolism of catecholamines [18]. The result of increased availability and decreased metabolism is a massive abundance of catecholamines released in synaptic clefts, which can produce a variety of physiologic consequences including addiction, psychiatric changes, neurologic damage, cardiovascular damage, and gastrointestinal damage [19].
Multiple studies have linked long-term methamphetamine use to alterations of brain structure and biochemistry [20]. The common consequences of these changes have included impairments of memory, learning, language skills, motor skills, and visuo-constructional abilities; high rates of psychiatric manifestations including psychosis, anxiety, and depression have also been observed [21,22,23][21][22][23]. Methamphetamine also has been shown to deplete dopamine, serotonin, and their metabolites in several brain regions [24]. The possible mechanisms of methamphetamine-induced brain changes are neurotoxicity and inflammation [25]. Excess dopamine auto-oxidizes in the cytoplasm of neurons, enabling significant production of reactive oxygen species [26]. Subsequent oxidative stress leads to significant dysfunction of neurons, terminal degeneration, and apoptosis [27]. Psychostimulants also cause excitotoxic damage by stimulating glutamate release [26,28][26][28].
Methamphetamine is proposed to upregulate inflammatory processes, in part, by activating toll-like receptor 4 (TLR4) [29]. The TLR4 signaling pathway is a well-studied component of the innate immune system’s proinflammatory cytokines and chemokines [30]. Methamphetamine-induced TLR4 signaling increases NF-κB activation of microglia and mRNA expression for the proinflammatory cytokine IL-6 in the ventral tegmental area (VTA) [29]. The downstream effect of this TLR4-IL-6 signaling in the VTA is neuroinflammation and an elevation of dopamine in the NAc shell [29]. These mechanisms of dopamine-induced neurotoxicity and inflammation cause disruption of endogenous dopamine signaling by destroying post-synaptic neurons and dopamine terminals [26].
Long-term methamphetamine abusers have been found to have reduced striatal dopamine levels [31]. A further study concluded that the dopamine levels in the putamen were as severely diminished as liken to people with Parkinson’s disease [32]. Morphological changes visible on MRI also provide evidence for neurotoxicity from methamphetamine use. Prominent changes include decreased hippocampal sizes, enlarged striatum, and loss of grey matter in cingulate and limbic cortices [33,34][33][34].

2.2.1. Current Treatment of Methamphetamine Use Disorder

Currently, there are many studies on the behavioral effects of a large variety of pharmacologic classes that target different regions of the brain. However, most of these studies have been limited to small clinical trials, and there are currently non-FDA-approved medications to treat cocaine or methamphetamine addiction [4,35][4][35]. Additionally, there has been no reliable evidence of any current pharmacologic agents that reduce psychological distress or physical symptoms associated with methamphetamine use [36]. Throughout these studies, numerous classes of medications target different receptors, including GABAergic and dopaminergic. Among others, they are central to the addiction process as its activity has been associated with reward processing in the brain [3]. Some of the psychotropic pharmaceutical classes studied include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, and dopamine agonists [4,35][4][35].
Additionally, many inconsistent effects have been found in treatment with propranolol as an anxiolytic, and bupropion and mirtazapine for associated depression. At the same time, most consistently, the benefits include mild stimulatory agonists including dexamphetamine and methylphenidate for amphetamine withdrawal and naltrexone and topiramate [35]. Furthermore, GABA enhancers, including topiramate, and more recently, N-acetylcysteine, have shown some marginal benefit and may be beneficial in reducing cravings and relapse prevention [35,37][35][37]. While many attempts to treat methamphetamine use pharmacologically have not been consistently significant, observing the behavioral effects due to central neuromodulation of these therapeutics has led to further advancements such as the understanding of the neurophysiology of substance abuse and central reward systems. The limitations of these treatments are the lack of clinical studies to evaluate their effectiveness in the general population.
The medical community is focusing on OT as an emerging treatment for methamphetamine use given the lack of consistent response of previous alternative therapies. Recent studies in rodents and humans suggest that OT may modulate substance-induced behaviors in the context of methamphetamine and cocaine use and even enhance prosocial behavioral responses to 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) [38]. Additionally, there are decreased measured levels of OT peptides in states of chronic withdrawal, and oxytocin receptors are upregulated. For this reason, central neuromodulation of oxytocin pathways through activation of a variety of glutamate and dopamine receptors, among other mechanisms, may reliably alleviate specific symptoms of methamphetamine withdrawal [7]. Since there is growing evidence of oxytocin modulation of behavior in social stress, social anxiety, social cognition, and psychosis, OT may provide benefit through similar mechanisms in the treatment of methamphetamine use [5].

2.2.2. Oxytocin

The neuropeptide oxytocin is primarily known for its functions regarding parturition, lactation, and interpersonal attachment. Extensive evidence now supports oxytocin’s role in the complex physiology of addiction and the attenuation of anxiety, inflammatory, and stress responses [39,40][39][40]. Oxytocin is synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Most of the synthesized peptide is transported to the posterior pituitary for storage and secretion. A portion of oxytocin is released centrally from the PVN and SON to act on receptors throughout the brain, including portions of the cortex, olfactory system, basal ganglia, limbic system, and brainstem [39,41,42][39][41][42]. Oxytocin has been linked to various physiological processes related to drug addiction, including the hypothalamic-pituitary-adrenal axis stress response, the central amygdala relating to anxiety and fear, and antinociception, autonomic regulation via the brainstem [43,44][43][44]. The abundance of oxytocin receptors throughout the CNS supports the growing information regarding the function of this neuropeptide.
Research involving the intricate cycle of addiction has secured a place for oxytocin as a potential treatment for the disease. The addiction cycle includes drug consumption, intoxication, and reward; oxytocin interferes with these three stages via multiple proposed mechanisms. The promising effects of oxytocin on the drug addiction cycle can be partially attributed to its action on dopaminergic reward pathways, specifically the connection between the VTA and the NAc [45,46][45][46]. The hypothalamic PVN houses oxytocinergic projections that terminate in the NAc and other addiction-associated areas of the brain [47]. Administration of oxytocin reduces both the consumption of substances of abuse (SOA) and reward consequences while also decreasing some of the intoxicating effects of SOA in rodent studies [45,48,49][45][48][49]. The accumulating evidence that exhibits oxytocin’s interactions with neural substrates related to addiction makes this neuropeptide a promising treatment option for these destructive diseases.

2.3. Mechanism of Action

Improved techniques in neurobiology have identified a variety of locations for oxytocin receptors and different projections in the brain. Many central oxytocin receptors are involved in mood and social behavior located in the mesocorticolimbic system’s reward processing region. These projections operate mostly through GABA neurotransmitter pathways. Additional effects on behavior, sensation, and perception may be mediated through centrally released oxytocin that projects to other, diverse brain regions. The regions include the medial amygdala and CeA, SN, paraventricular thalamic nucleus, olfactory nucleus, hippocampus, brainstem, and spinal cord. Other regions include the lateral mammillary nucleus, ventral pallidum, globus pallidus, basal nucleus of Meynert medial preoptic area, dorsal raphe nucleus, tubercle, and lateral septum may also be involved [6,7][6][7]. Although the diverse effects of OT neuromodulation in methamphetamine abuse are not well understood, recent findings are suggestive that oxytocin interacts with dopamine, glutamate, GABA, and vasopressin receptors in these central nuclei [6]. Even more so, oxytocin has also been shown to enhance connectivity between frontal and other cortical regions [8].
In terms of its role in substance abuse, the mechanism of oxytocin neuromodulation is thought to be through glutamate receptors, which remain active in the various regions involved in forming memories, learning, and reward processing [6]. Further findings suggest oxytocin neuromodulation resists alterations to glutamate–dopamine and glutamate–GABA-A interactions through drug-induced effects on glutamate transmission. Current theories suggest that these interactions enhance GABA’s inhibitory effects on glutamate and dopamine neurons and reduce mesocorticolimbic dopamine and corticolimbic glutamatergic pathways [6,7][6][7]. In addition to modification at the synaptic junction, OT has demonstrated physiologic effects on astrocyte function by reducing glial fibrillary acidic protein (GFAP) expression. GFAP is a protein that is increased in drug-induced states, can alter neural plasticity, and has associated neurotoxic properties. Reduced levels of GFAP ultimately result in reduced glutamate transmission through decreased GLT-1 transport of glutamate to the cell surface. Therefore, these findings suggest an additional explanation for oxytocin’s mechanism in attenuating drug-associated behaviors. Through restoring GFAP expression and, therefore, reversal of astrocyte function, OT may indirectly affect glutamatergic transmission opposing drug-induced behaviors [6].

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