METH is a lipophilic compound that rapidly crosses the blood-brain barrier (BBB) and accumulates in the brain. Its pharmacological effects stem primarily from the disruption of monoaminergic neurotransmission and its downstream neurotoxic consequences.

METH induces neurotoxicity via a combination of oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. These processes are closely interrelated, amplifying each other and contributing to long-term neuronal damage and neurodegeneration.

METH abuse induces neurological damage that manifests as cognitive impairment, psychiatric symptoms, and motor dysfunction, with clear distinctions between the acute and chronic phases of use. In the acute phase, symptoms include euphoria, anxiety, paranoia, and psychomotor agitation, which are primarily caused by the short-term overactivation of neurotransmitter systems (Cruickshank and Dyer, 2009). By contrast, the chronic phase is characterized by persistent cognitive decline, worsening psychiatric symptoms, and progressive motor dysfunction as neuroinflammation and neuronal loss become more pronounced (McCann et al., 2008).

Auxiliary examinations, particularly neuroimaging and neurochemical analyses, play a crucial role in identifying functional and structural changes in the nervous system caused by METH abuse. These findings provide objective evidence supporting the previously discussed clinical manifestations and underlying neurotoxic mechanisms.

Neuroimaging studies, including positron emission tomography (PET) and magnetic resonance imaging (MRI), have consistently demonstrated widespread abnormalities in brain regions involved in cognitive control, emotional regulation, and motor function. PET scans have revealed a significant reduction in dopamine levels in the striatum, including the caudate nucleus and putamen, which disrupted dopamine signaling. This reduction correlated with impaired motor function and the development of compulsive drug-seeking behaviors (Sekine et al., 2001). Concurrently, altered glucose metabolism in the orbitofrontal cortex and limbic regions reflects energy deficits and mitochondrial dysfunction, contributing to the severity of psychiatric symptoms, such as paranoia, agitation, and mood disturbances (Chang et al., 2007).

MRI studies have further identified gray matter atrophy in the prefrontal cortex, medial cingulate gyrus, and hippocampus, regions that are critically involved in memory, decision-making, and emotional regulation (Thompson et al., 2004). In particular, hippocampal damage is correlated with memory impairment and learning difficulties, whereas prefrontal atrophy contributes to deficits in executive function and increased impulsivity. In addition, diffusion tensor imaging highlighted reduced white matter integrity within the corpus callosum and thalamic radiation, suggesting demyelination and impaired neural connectivity. These changes can result in slower information processing, reduced motor coordination, and increased cognitive inflexibility (Yang et al., 2018).

Magnetic resonance spectroscopy provides complementary biochemical evidence of METH-induced neurotoxicity. Reduced concentrations of N-acetyl aspartate and total creatine in the basal ganglia are markers of neuronal loss and impaired energy metabolism, which correlate with cognitive dysfunction and motor deficits (Nordahl et al., 2005). Conversely, increased levels of choline and myo-inositol in the prefrontal cortex suggest neuroinflammation and glial activation, consistent with the inflammatory processes observed in METH-induced neurotoxicity (Chang et al., 2007).

Behavioral assessments aligned closely with these imaging findings, offering a clinical perspective on the neurological damage caused by METH abuse. Chronic METH users exhibit significant deficits in working memory, executive function, and attention, which reflect structural and functional changes in the prefrontal cortex and hippocampus (McCann et al., 2008). Motor impairments, including fine motor dysfunction, reduced coordination, and slower reaction times, are consistent with basal ganglia damage and white matter disruption. Psychiatric symptoms, such as paranoia, anxiety, and psychosis, further correlate with the observed abnormalities in the limbic and orbitofrontal regions (Zweben et al., 2004).

Collectively, these neuroimaging and behavioral findings illustrate the extensive impact of METH on both brain structure and function. They provide a clear link between biochemical disruptions, such as dopamine depletion and neuroinflammation, and the resulting cognitive, psychiatric, and motor symptoms observed in chronic METH abusers.

Cognitive-behavioral therapy (CBT) is a well-established standard treatment for addressing cognitive impairment caused by METH abuse (Lee and Rawson, 2008). CBT primarily improves cognitive deficits through structured psychosocial interventions targeting behavioral patterns and decision-making processes. Although CBT has shown considerable promise, its long-term effectiveness can be influenced by factors, such as treatment adherence, patient motivation, and the availability of resources for prolonged interventions (Apuy et al., 2023).

In addition to behavioral therapies, pharmacological approaches have demonstrated potential benefits. A double-blind randomized controlled trial revealed that atomoxetine, a selective norepinephrine reuptake inhibitor, effectively enhanced cognitive functions, such as memory, inhibitory control, and attention, in METH users (Rabiey et al., 2022). Similarly, modafinil, a dopamine reuptake inhibitor, has been shown to improve recognition memory impairment in METH users. However, the beneficial effects of modafinil have been primarily observed in mice, and further clinical studies are necessary to validate its efficacy and safety in humans (González et al., 2014).

Immunotherapy strategies, such as MHC/neuroantigen peptide constructs, have emerged as experimental approaches for treating METH-induced learning and memory deficits. Although preclinical data show promise (Loftis et al., 2013), their clinical applicability remains unclear owing to challenges, such as immune response variability and limited human trials. Similarly, the neuroprotective agent baicalin has demonstrated potential in mitigating METH-induced amnesia and cognitive impairment in animal studies; however, these findings were primarily derived from experiments in rodent models, which limits their immediate translational impact (Wong et al., 2014).

In addressing motor dysfunction induced by METH, transcranial magnetic stimulation has shown potential for restoring motor control by modulating cortical excitability (Edinoff et al., 2023). Although transcranial magnetic stimulation is a noninvasive and promising intervention, its accessibility, treatment duration, and cost-effectiveness remain significant concerns for real-world clinical applications. In preclinical studies, the fragment C domain of the tetanus toxin (Hc-TeTx) has been shown to alleviate METH-induced neurotoxicity and motor deficits in animal models; however, human studies are lacking thus far (Mendieta et al., 2016).

Additionally, physical exercise has been recognized as an effective adjunctive intervention for mitigating the cognitive and motor impairments associated with chronic METH use. Exercise modulates dopamine levels and enhances neuroplasticity, offering a nonpharmacological approach for long-term recovery (Morais et al., 2018). However, its efficacy may vary depending on patient compliance, exercise intensity, and duration, which poses challenges to its widespread implementation.

While these treatment approaches, both behavioral and pharmacological, hold promise for alleviating METH-induced neurological damage, their long-term efficacy, potential side effects, and real-world feasibility remain significant concerns. Future clinical trials and translational studies are required to better evaluate these interventions and establish comprehensive treatment protocols for METH users.

Cocaine impairs vascular function by causing vasoconstriction, reducing cerebral blood flow, and decreasing tissue oxygenation. These effects are partly due to the prolonged activation of astrocytes (Liu et al., 2022). Animal studies have shown that cocaine use leads to cortical microischemia and prefrontal cortical ischemia (Ren et al., 2012), which disrupt the neurovascular network and impair brain function (Du et al., 2020). Chronic use may also trigger cerebral angiogenesis via the HIF-VEGF pathway as a compensatory response to ischemia (Yin et al., 2017). Although angiogenesis may initially appear beneficial by enhancing neuroplasticity, it can also exacerbate vascular pathology by destabilizing the BBB.

Additionally, cocaine induces apoptosis in cerebral vascular smooth muscle cells, contributing to vasoconstriction and ischemia, resulting in significant neurological damage (Fonseca and Ferro, 2013). Cocaine-induced vasoconstriction and vasculitis can lead to severe neurological complications, including headaches, seizures, aneurysms, strokes, and subarachnoid hemorrhages (Farooque et al., 2020).

The neurological effects of cocaine include diffuse leukoencephalopathy, which is characterized by vasospasms, cerebral ischemia, and posterior reversible leukoencephalopathy (Rowbotham and Lowenstein, 1990; Li et al., 2018). It also induces psychiatric symptoms, such as euphoria, hypervigilance, interpersonal sensitivity, impaired judgment, paranoid delusions, hallucinations, and bizarre behaviors (Roncero et al., 2013). Chronic cocaine exposure has been linked to an increased risk of Parkinson’s disease, as it promotes α-synuclein overexpression in dopamine neurons, causing resting tremors and neurotoxic damage (Mash et al., 2003).

Imaging studies have demonstrated that chronic cocaine users often exhibit brain atrophy and reduced gray and white matter volumes, particularly in the limbic regions essential for emotional processing and reward (Bartzokis et al., 2000; Rando et al., 2013).

Calcium channel blockers, such as amlodipine, have shown promise in preventing cocaine-induced vascular toxicity by lowering blood pressure and reducing headache frequency (Malcolm et al., 2002; Du et al., 2021). Decompressive craniectomy is an effective treatment for cocaine-induced ischemic stroke (Algahtani et al., 2021). Modified CBT addresses the cognitive dysfunction associated with cocaine abuse (Aharonovich et al., 2018). In emergencies involving agitation, rapid symptom control can be achieved using lorazepam or midazolam injections (Nobay et al., 2004). Seizures, if recurrent, should be treated with intravenous benzodiazepines, and status epilepticus should be managed according to established protocols (Meierkord et al., 2010).

Synthetic cathinones primarily enhance the release and inhibit the reuptake of monoamines, such as dopamine, norepinephrine, and serotonin. This results in excessive synaptic monoamine concentrations, the overstimulation of postsynaptic receptors, and excitatory neurotoxicity. For instance, mephedrone increases both dopamine and serotonin release, whereas α-PVP primarily targets dopamine and norepinephrine transporters (Simmler et al., 2013). Chronic exposure to these drugs depletes presynaptic monoamine stores, impairs long-term neuronal signaling, and induces neurodegeneration (Angoa-Perez and Kuhn, 2024).

The excessive release of monoamines promotes ROS formation through the auto-oxidation of dopamine and norepinephrine. This overwhelms the neuronal antioxidant defenses, causing oxidative damage to lipids, proteins, and DNA. Synthetic cathinones also impair mitochondrial function, reduce ATP production, and increase the opening of mitochondrial permeability transition pores. This cascade leads to neuronal apoptosis and energy deficits, particularly in the prefrontal cortex and hippocampus (Leong et al., 2020).

Synthetic cathinones disrupt glutamatergic signaling by enhancing glutamate release and impairing astrocytic uptake (Leong et al., 2020). Elevated extracellular glutamate levels activate NMDA and AMPA receptors, resulting in excessive calcium influx into neurons (Hu et al., 2004). Calcium overload triggers the activation of calcium-dependent enzymes, including calpains and caspases, which degrade cytoskeletal proteins and lead to neuronal death (Zhang and Bhavnani, 2006).

The neurotoxic environment created by synthetic cathinones activates microglia and astrocytes, leading to the release of proinflammatory cytokines, such as IL-1β and TNF-α. This inflammatory response exacerbates the neuronal damage and promotes chronic neuroinflammation (Marusich et al., 2022). Studies have shown that α-PVP and mephedrone significantly increase microglial activation in the striatum, contributing to long-term neurodegeneration (Buzhdygan et al., 2021).

Ketamine abuse commonly manifests as dissociative symptoms, such as altered consciousness, detachment from the environment, and sensory loss (Vlisides et al., 2018). High doses may lead to the “K-hole” phenomenon, characterized by extreme dissociation without loss of consciousness (Malhotra et al., 1996). Chronic abuse is associated with cognitive impairments, including memory and attention deficits, psychotic-like symptoms (hallucinations and delusions), and motor dysfunction (Morgan et al., 2004).

Neuroimaging studies have provided critical insights into ketamine-induced neurotoxicity. PET scans have revealed altered cerebral blood flow, with increases in regions, such as the anterior cingulate cortex, and decreases in the cerebellum (Holcomb et al., 2001). MRI studies have demonstrated reduced prefrontal gray matter volume and impaired white matter integrity in chronic users (Liao et al., 2011). In severe cases, CT scans reveal widespread brain atrophy (Liu et al., 2021).

Gradual tapering of ketamine is recommended to minimize withdrawal symptoms because abrupt cessation may result in hyperalgesia and sensory disturbances (Mitchell, 1999). Experimental approaches, such as miR-34a modulation, 17β-estradiol supplementation, and L-carnitine administration, show promise in mitigating ketamine-induced neurotoxicity (Li et al., 2013; Liu et al., 2013). Although most cognitive impairments resolve after cessation, episodic memory and attention deficits may persist, highlighting the need for long-term follow-up (Morgan et al., 2004).

Vit B12 is a cobalt-containing molecule essential for various biochemical reactions, primarily in its active forms adenosylcobalamin and methylcobalamin (Froese et al., 2019). These forms are critical in the pathogenesis of N₂O poisoning. N₂O exposure oxidizes the cobalt ion in Vit B12 from its +1 to +3 oxidation state, irreversibly inactivating the molecule (Garakani et al., 2016). This inactivation disrupts key enzymatic reactions, including the conversion of methylmalonyl-CoA to succinyl-CoA by methylmalonyl-CoA mutase and the synthesis of methionine from homocysteine (Hcy) by methionine synthase (Figure 2). The downstream biochemical consequences of this disruption form the basis for understanding the neural damage and clinical manifestations induced by N₂O.

The accumulation of methylmalonic acid (MMA) and Hcy because of these disruptions leads to oxidative damage and impaired methylation. Methionine, which is converted into S-adenosylmethionine (SAM), is crucial for methylation processes affecting DNA, RNA, proteins, and lipids. Disruption of SAM synthesis affects cellular integrity and function. Understanding these mechanisms elucidates the biochemical basis of N₂O-induced neurotoxicity and its clinical manifestations.

The molecular disruptions outlined above initiate a series of cascading effects, leading to neural damage through oxidative stress, excitotoxicity, and demyelination. The following sections detail the interconnected mechanisms underlying N₂O-induced neurotoxicity.

N₂O-induced injuries are classified into acute, subacute, and chronic phases. Acute manifestations include hypoxia, frostbite, and psychiatric symptoms. Subacute and chronic injuries predominantly feature demyelination of the nervous system and megaloblastic anemia, with up to 96% of patients experiencing neurological damage (Oussalah et al., 2019; Dawudi et al., 2024).

Spinal Cord Lesions: Symptoms include gait instability, sensory deficits, and motor weakness, often progressing to paraplegia in severe cases (Choi et al., 2019; Mair et al., 2023). Peripheral neuropathy manifests as numbness, tingling, and limb weakness, predominantly affecting the lower extremities (Winstock and Ferris, 2020). Cognitive and psychiatric symptoms include memory impairment, disorientation, and psychiatric conditions, such as paranoia and agitation.

Based on clinical experience, the diagnostic criteria for neurological damage due to long-term N₂O inhalation include the following: ① A history of N₂O exposure, particularly frequent short-term inhalations. ② Subacute or chronic progression of symptoms indicating neurological impairment. ③ MRI and electrophysiological evidence of damage to the spinal cord and/or peripheral nerves. ④ Exclusion of other potential causes, such as immune, metabolic, infectious, toxic, and neoplastic conditions, via auxiliary tests. When young patients exhibit symptoms, such as deep or superficial sensory disturbances, motor dysfunction, cognitive deficits, or psychiatric issues, further investigation is warranted. Notably, if these symptoms coincide with an inverted “V”-shaped T2 hyperintensity on spinal MRI, elevated serum Hcy and MMA levels, and normal or reduced Vit B12 levels, it is crucial to inquire about past N₂O inhalation. A confirmed history of N₂O use, along with the exclusion of other causes, supports the diagnosis.

For patients exhibiting neurological symptoms, it is crucial to differentiate between various diseases that may present similarly, such as Guillain-Barré syndrome, multiple sclerosis, and copper deficiency myelopathy. Accurate diagnosis is essential for effective treatment and management of these conditions.

Guillain-Barré syndrome typically follows a preceding infection and manifests as an acute onset of symptoms that progressively worsen, usually peaking around 2 weeks. Cerebrospinal fluid examination in such cases may reveal protein-cell dissociation. Multiple sclerosis predominantly affects women and is characterized by a relapsing course. Brain MRI often shows the characteristic Dawson’s fingers, whereas spinal cord lesions usually extend to fewer than two vertebral segments. In multiple sclerosis, cerebrospinal fluid often contains oligoclonal IgG bands. Copper is a vital cofactor for methionine synthase, and its deficiency can impair the enzyme’s function, disrupting methylation reactions. This disruption leads to neurological and hematological damage similar to that seen in N₂O abuse, including posterior column lesions in the cervical and thoracic spinal cord, demyelination, or axonal injury of peripheral nerves. These manifestations are challenging to differentiate clinically and radiologically. Copper deficiency myelopathy is more likely to occur in patients who have undergone upper gastrointestinal surgery, typically between the ages of 50 and 60 years, and is more common in women than in men. Biochemical tests in these patients may reveal decreased serum copper and ceruloplasmin levels (Kumar et al., 2004; Jaiser and Winston, 2010) (Table 2).

Immediate cessation of N₂O exposure is critical. Vit B12 replacement therapy, typically administered intramuscularly, is the cornerstone of treatment (Marotta and Kesserwani, 2020). Adjunctive supplementation with folic acid and vitamin B6 enhances recovery by supporting the methylation cycles and reducing neurotoxicity (Algahtani et al., 2020). Early intervention improves the prognosis, although severe axonal damage may result in permanent deficits.

Heroin-induced oxidative stress disrupts the balance between oxidation and antioxidation (Xu et al., 2006), leading to neuronal death and BBB disruption during withdrawal (Sharma and Ali, 2006). Studies have indicated that heroin reduces mitochondrial potential and alters the Bcl-2/Bax ratio, thereby affecting cell survival (Cunha-Oliveira et al., 2007). Chronic use activates microglial cells in the cortical gray matter, thereby promoting inflammation and neurotoxicity. Heroin-related brain hypoxia results primarily from respiratory depression, which exacerbates ischemic risk (Solis et al., 2017).

Heroin injection significantly increases the risk of cerebrovascular complications, including ischemic and hemorrhagic stroke (Sloan et al., 1991). Inhalation methods, such as “chasing the dragon,” are associated with leukoencephalopathy, characterized by progressive motor and cognitive impairments, ataxia, and spastic paresis (Keogh et al., 2003). MRI revealed symmetrical white matter lesions in the corticospinal tract (Wolters et al., 1982), while diffusion tensor imaging highlighted impaired white matter connectivity due to myelin damage rather than axonal injury (Bora et al., 2012).

Heroin also induces psychiatric symptoms, such as depression, anxiety, impulsiveness, and interpersonal sensitivity (Pasternak, 2012). Cognitive impairments, including reduced memory, impaired impulse control, and decision-making difficulties (Tolomeo et al., 2021), are commonly observed.

Calcium channel blockers and opioid antagonists, such as naltrexone, have shown potential for managing heroin addiction and ischemic stroke (Peyravian et al., 2022). Emerging therapies, including nanotechnology-based drug delivery, are promising for reversing long-term neuronal damage (Nguyen et al., 2021).

Although cocaine and heroin have profound neurobiological and vascular effects, their mechanisms of action differ significantly. Cocaine primarily acts as a psychostimulant by increasing monoamine neurotransmitter levels, leading to excitotoxicity and vascular damage. Heroin, an opioid, primarily modulates G protein-coupled receptor activity and affects neuronal excitability and reward pathways. Despite these differences, both substances contribute to oxidative stress, neuroinflammation, and cognitive impairment, highlighting the overlapping pathological pathways.

The vascular effects of cocaine include angiogenesis and vasoconstriction, in contrast to heroin’s predisposition to ischemic and hemorrhagic complications. Both substances are linked to leukoencephalopathy; however, heroin-induced leukoencephalopathy lacks the spongiform quality characteristic of prion disease. Understanding these similarities and differences is critical for developing targeted interventions for substance abuse.