The use of amphetamine-type stimulants (i.e., methamphetamine (MA), amphetamine, and methylenedioxy-methamphetamine) is on the rise worldwide. According to the United Nations Office on Drugs and Crime report, there were an estimated 27 million individuals using amphetamine-type stimulants in 2019 (1). Meanwhile, MA is the most widely used in the amphetamine-type stimulants group (2). A pernicious social wonder with far-reaching mental, familial, and economic adversities, which contribute to robbery, murder, suicide, aggression, and divorce, has been attributed to this drug (3).
1.1. Neurobiology, Clinical Symptoms, Diagnosis, and Treatment of Methamphetamine Use Disorder
The MA, due to its lipophilic nature, easily passes the blood-brain barrier, where it stimulates the excessive release of monoamines (i.e., dopamine, norepinephrine, and serotonin) in the monoaminergic nerve terminals. There are several mechanisms that contribute to this release of neurotransmitters, including (a) the redistribution of monoamines from synaptic vesicles to the cytosol; (b) the reversal of monoaminergic transporter function and release of neurotransmitters into the extraneuronal space; and (c) the reduction of metabolism of monoamines by the suppression of monoamine oxidase function. Collectively, elevated neurotransmitters in nerve terminals promote neurotoxicity through the degeneration of monoaminergic terminals, apoptosis, oxidative stress, and neuroinflammation (4-6).
The MA, known as a sympathomimetic agent, acts rigorously on the central and peripheral nervous systems and the cardiovascular system (7, 8). The clinical signs depend on the duration, dose, and route of drug use. In general, the clinical picture of acute MA use is euphoria, decreased need for sleep and food, increased alertness and energy, and overactivation of the sympathetic nervous system, producing a fight-or-flight response (9, 10). In a study of emergency department referrals, seizures, chest pain, tachycardia, palpitations, hypertension, tachypnea, visual hallucinations, auditory hallucinations, paranoia, grandiosity, talkativeness, suicidal ideation, homicidal ideation, violence, and disorientation have been significantly more common in patients who tested positive for MA (11).
The repeated use of MA causes tolerance; therefore, some MA users in order to re-experience the pleasure effect take higher doses; as a result, long-term consumption, along with increasing the dose of the drug, can exacerbate the symptoms. The excessive release of dopamine by MA has destructive effects on nerve endings of dopaminergic neurons in the brain. Neuroimaging studies of chronic MA users have shown a greater number of blood flow defects and ischemic lesions (12) and severe functional and structural changes in brain regions related to memory and mood. The most common symptoms of chronic abuse include mood disturbances, anxiety, depression, hallucinations, paranoid ideas, homicidal ideas, violence, out-of-control rages, psychosis, relapse tendency, and neurocognitive dysfunction (3). The discontinuation of MA is also associated with withdrawal syndromes, such as somnolence, craving, depression, anxiety, suicidal ideation, anhedonia, and cognitive impairment (13-15).
The diagnosis of methamphetamine use disorder (MUD) is characterized by the diagnostic and statistical manual of mental disorders, fifth edition, and includes the escalation of drug use, tolerance, withdrawal, and drug craving in users (16). Currently, there is no Food and Drug Administration (FDA)-approved effective intervention to prolong abstinence and prevent relapse from MA (17). A systematic review surveyed the efficacy of numerous medications for the treatment of MUD, including dopamine agonists, antidepressants, anticonvulsants, antipsychotics, and opioid antagonists. This review showed that none of these medications was successful in treating MUD (18). Other approaches, such as behavioral therapies, have been associated with promising results; however, few studies have examined these interventions, and further studies are needed to clarify the effectiveness of these approaches (19).
The vagus nerve is known as the major part of the autonomic nervous system and involves in the maintenance of homeostasis by the regulation of the neuroendocrine-immune axis and cardiovascular system (20, 21). The disturbance of the balance between the sympathetic and parasympathetic nervous systems and overactivation of the sympathetic and immune systems have been reported in MUD (8, 9). The current study hypothesizes the role of potential neuroprotective mechanisms of noninvasive vagus nerve stimulation (VNS) and the neurobiological pathways underlying the processes in the treatment of MUD.
2. Evidence Acquisition
2.1. Vagus Nerve Stimulation Methods
Currently, invasive vagus nerve stimulation (iVNS) is approved by FDA for the treatment of refractory epilepsy and drug-resistant depression. Transcutaneous vagus nerve stimulation (tVNS) is another technique for vagal electrical stimulation that is known as a noninvasive method and, unlike iVNS, does not require surgery and has better safety and tolerability among users. The tVNS is performed in two ways; one is via the cervical branch of the vagus nerve in the neck, and the other is via the auricular branch of the vagus nerve in the outer ear. The common side effects of tVNS are tingling, redness, itching, and less pain around the site of stimulation (22, 23). The tVNS is used to treat various disorders, such as depression (24), migraines (25), tinnitus (26), chronic pain (27), and epilepsy (28).
3.1. Neuroimmune Mechanisms of Vagus Nerve Stimulation in the Control of Inflammatory Response
The MA induces neurotoxicity through the hyperactivation of the neuroimmune system and produces pro-inflammatory cytokines (e.g., interleukin-1 beta, interleukin-6, and tumor necrosis factor α (TNF-α)). Exposure to MA promotes the disruption of blood-brain barrier integrity and infiltration of pro-inflammatory cytokines from microglia and astrocytes, which might lead to neurodegeneration. In addition, excessive monoamines induce oxidative stress and subsequently mitochondrial damage and endoplasmic reticulum stress. The repeated use of MA leads to the depletion of monoamine stores, damage to nerve terminals, and apoptosis. Therefore, these neurotoxic mechanisms might contribute to neuropsychiatric complications and cognitive dysfunction and prolong addictive behavior (29-33).
Recent documents have suggested anti-inflammatory effects for VNS, which might be central and peripheral (34, 35). Neuroimmune and neuroendocrine systems are involved in vagal anti-inflammatory pathways (36). Two pathways are activated by vagal afferent fibers through peripheral inflammatory mediators. These mediators, such as endotoxins and pro-inflammatory cytokines, stimulate vagal afferent fibers and, subsequently, vagal afferents send inflammatory information to the dorsal vagal complex which consists of the nucleus tractus solitarii (NTS), the area postrema (AP), and the dorsal motor nucleus of the vagus (37, 38). After the dorsal vagal complex receives inflammatory input, two distinct mechanisms are initiated: The hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway (CAP). In the HPA axis, vagal inputs activate NTS neurons from the A2 noradrenergic group, which projects to neurons in the hypothalamus that contain corticotropin-releasing factor. These neurons stimulate the release of adreno-corticotrophin hormone by the pituitary gland, a hormone that activates the release of glucocorticoids from the adrenal glands and suppresses peripheral inflammation (36, 39). The HPA axis can also be centrally activated by pro-inflammatory cytokines reaching the AP, a circumventricular organ that lacks a normal blood-brain barrier (40). The second mechanism, known as the CAP, is activated by vagal efferent fibers that project to enteric neurons in the gut and release acetylcholine near macrophages. This neurotransmitter binds to alpha-7 nicotinic acetylcholine receptors located on the membrane of macrophages and suppresses the release of TNF-α (39, 41, 42).
3.2. Role of Vagus Nerve Stimulation in Balancing the Autonomic Nervous System and Regulating Cardiovascular Function
The acute consumption of MA causes a rapid release of central and peripheral monoamine neurotransmitters and a marked increase in sympathetic tone, causing vasoconstriction, hypertension, tachycardia, bronchodilation, and hyperthermia (30). In addition, MA overdose is associated with sudden cardiac death and is the second leading cause of death, especially among young consumers (43). Furthermore, the chronic consumption of MA is associated with vagal tone dysfunction and a decrease in heart rate variability (HRV), cardiovascular tissue damage induced by an inflammatory response, pulmonary hypertension, cardiac arrhythmias, and heart failure due to electrical remodeling of cardiac tissue (44, 45). It has been reported that VNS alters the balance between the activation of sympathetic and parasympathetic nervous systems toward the dominance of parasympathetic tone (46-48). Therefore, it might be an effective approach to various disorders characterized by sympathetic hyperactivity, such as MUD.
Noninvasive VNS has been shown to increase HRV in healthy participants, which is a biomarker for enhancing vagus nerve outflow to the heart and inhibiting sympathetic hyperactivity (49). Numerous studies have shown that iVNS is a novel intervention to improve patients with heart failure. Similar to autonomic system dysfunction in MA users, heart failure is characterized by a decrease in vagal tone and an increase in sympathetic outflow (50-53). Several mechanisms have been described for the clinical benefits of VNS in heart failure, including heart rate reduction, antiarrhythmic effects, and suppression of proinflammatory cytokines (54-56).
3.3. Role of Vagus Nerve Stimulation in Modulating Mood Disturbances
Mood/affective disturbances, such as anxiety and depression, are characteristic withdrawal symptoms during abstinence from the chronic abuse of MA, which might persist for 2 - 5 years after discontinuation of the drug (57, 58). Chronic MA use leads to structural and functional changes in the monoaminergic system in the reward circuit, including the limbic system, striatum, and paralimbic regions, which are associated with anxiety and depressive symptoms (9, 59). Therefore, improving affective withdrawal symptoms might reduce the risk of MA relapse.
Numerous studies have demonstrated the antidepressant and anxiolytic effects of VNS on depressive and anxiety disorders through the modulation of monoaminergic neurotransmitters, alteration of neuronal activity, suppression of neuroinflammatory responses, neurogenesis in the hippocampus, and control of the gut-microbiota-brain axis (60-64). The effect of VNS on the treatment of mood disturbances is partly related to the innervation of afferent fibers to the NTS in the medulla oblongata. These fibers are directly and indirectly further projected to other brain regions, such as the orbitofrontal cortex, thalamus, insula, hypothalamus, amygdala, and reticular formation, responsible for the control of anxiety and depression (61, 62, 65). According to these findings, neuroimaging studies have shown that VNS can improve depressive symptoms by altering the activity of cortical-limbic-thalamic-striatal neural circuits that are disrupted in depression (61, 62, 66-68). Anatomically, the vagus nerve sends direct afferent sensory information to the NTS and from this region to the locus coeruleus (LC) and the dorsal raphe nucleus (DRN). As previously mentioned, the LC and NTS project numerous mood-regulating limbic and cortical brain structures (69). Therefore, VNS can increase the concentration of noradrenaline from noradrenergic neurons in the LC and serotonin from the DRN (60, 70, 71). These events could restore the depletion of monoamines, which are a major cause of depressive and anxiety symptoms in chronic MA users.
The effect of VNS on biogenic amines is consistent with the mechanism of action of antidepressants. The electrophysiological recordings and microdialysis studies of neurons in the DRN and the LC show an increase in neuronal activation and release of serotonin and norepinephrine after acute and chronic VNS therapy (72). An animal study has shown that the lesion of noradrenergic and serotonergic systems by 6-hydroxydopamine abolishes the antidepressant and anxiolytic-like effects induced by VNS (73).
There are controversial findings regarding the dopaminergic system and its relationship to VNS. Positron emission tomography performed by Conway et al. (66) showed that long-term VNS therapy increases the cerebral metabolic rate of glucose in the ventral tegmental area (VTA), the primary brainstem area of dopamine. This finding is consistent with the findings of a study by Carpenter et al. who demonstrated an increase in homovanillic acid in the cerebrospinal fluid (CSF) of patients with chronic major depression following VNS treatment (60). In contrast to these findings, a preclinical study using electrophysiological recordings has shown a decrease in neuronal firing rate in the VTA after 2 weeks of VNS therapy (71).
The neurogenesis theory in depression describes that stress causes the impairment of neurogenesis in the hippocampus, which can also be restored by antidepressants (74, 75). Preclinical studies have shown that VNS enhanced the proliferation of neural progenitor cells in the dentate gyrus of the hippocampus in an animal model of depression (63, 76). A similar effect was also observed after the chronic administration of fluoxetine (77). Chronic MA consumption is associated with impairments in the proliferation, differentiation, and survival of neural progenitor cells in the dentate gyrus. These impairments contribute to memory impairment, mood disorders, drug seeking-behavior, and drug taking-behavior (78-80). The current study suggests that VNS might reverse the negative effects of MA on hippocampal neurogenesis and reduce relapse during MA abstinence.
The growing evidence elaborated that targeting of gut microbiome ameliorates mood disorders in patients with depression and anxiety (81, 82). The influence of the microbiota on brain function and the modulation of mood and behavior is achieved through the vagus nerve (64). Animal studies have revealed that MA causes gut dysbiosis, which can be associated with anxiety-like behaviors (83, 84). Therefore, the present study hypothesizes that VNS reverses MA-induced gut dysbiosis and improves depression and anxiety in drug users. The microbiota components can activate vagus nerve afferent fibers directly or indirectly through gut endocrine cells. Activated vagus nerve afferent fibers stimulate the central nervous system via the central autonomic network and, in this way, affect psychiatric disorders and other stress-induced and inflammatory diseases. As previously mentioned, vagus nerve afferent fibers stimulate efferent fibers via inflammatory reflex and decrease gut inflammation and intestinal permeability by tight junction reinforcement, restoring dysbiosis. Studies have reported a low vagal tone in inflammatory bowel disease. Therefore, VNS can increase vagal tone and improve homeostasis in the gut-microbiota-brain axis (37, 85).
The concentrations of pro-inflammatory cytokines are increased in the peripheral circulation and the CSF in patients with depression (86). Similarly, the serum levels of pro-inflammatory cytokines are increased in MA abusers (87). Therefore, VNS might have a protective effect on the treatment of depression via the inhibition of pro-inflammatory cytokines.
The treatment of MUD by clinicians is difficult because it is associated with repeated relapses after abstinence from drugs. Moreover, intensive MA use is accompanied by physiological deficits, such as cardiovascular pathologies and mood disorders. Some of the disorders might even lead to death. The hypothesis of this study suggests that noninvasive VNS, auricular tVNS, might be effective as a complementary therapy in combination with current treatments in the management of MUD, especially during withdrawal from MA abstinence. Given the broad spectrum of MA adverse effects, there is an urgent need to develop new interventions for the treatment of MUD.
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