The Central Nervous System (CNS) comprises nerve cells and neuroglia that are susceptible to damage caused by various destructive factors [
1,
2,
3,
4,
5,
6,
7,
8]. Methamphetamine (METH) was first manufactured during World War II [
9]. However, its illicit use and recreational consumption have become significant concerns in many countries, despite its therapeutic applications in conditions like memory disorders, hyperactivity, narcolepsy, and obesity, today; it is used illegally and for recreation [
10,
11,
12]. Research has indicated that this substance can have side effects on the respiratory, cardiovascular, and nervous systems [
13,
14]. Individuals who use METH are susceptible to experiencing a range of emotional and cognitive effects. These include feelings of euphoria, increased energy and alertness, feelings of increased physical and mental performance, hallucinations, paranoia, anxiety, and increased productivity [
9,
11]. Unfortunately, despite the documented reports of irreversible side effects associated with the misuse of this substance, its prevalence continues to rise, particularly among the younger population worldwide [
15]. Research studies have demonstrated that METH can disrupt the activities of neurotransmitters in the CNS, including dopamine, serotonin, and norepinephrine [
16,
17,
18]. Animal model studies have revealed that METH has the ability to release dopamine-containing vesicles stored within neurons and inhibit the enzyme monoamine oxidase [
19]. Abnormal activity has been reported in specific CNS areas affected by dopamine and serotonin regulation, such as the striatum, prefrontal cortex, caudate nucleus, anterior cingulate, and amygdala, which may contribute to the increased risk of depression and aggressive behaviors in METH users [
20,
21,
22]. Furthermore, the degradation of dopaminergic neurons has also been observed following METH usage [
23]. METH’s ability to induce neurotoxicity is well documented and occurs through multiple pathways, including increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis [
24,
25,
26]. However, the precise mechanism underlying these actions is not fully understood [
8]. Neuroimaging studies investigating METH users have revealed alterations in both white and gray matter volume compared to healthy individuals in various regions of the CNS, including the cingulate, striatum, nucleus accumbens, hippocampus, parietal and occipital lobes, basal nuclei [
22,
27,
28,
29,
30,
31]. In addition to structural changes observed in the nervous system of individuals using METH, numerous studies have provided clear evidence of increased expression of oxidative stress, inflammatory, autophagy, and apoptosis markers in specific regions of the nervous system [
13,
32,
33,
34,
35,
36,
37]. Previous investigations have confirmed that METH can elevate apoptotic markers such as BAX, caspase 3, 8, and 9 in the amygdala and hippocampus [
38,
39]. Neurotrophic factors play a crucial role in the development and functioning of the nervous system, particularly brain-derived neurotrophic factor (BDNF), which is associated with neuronal plasticity, survival, and neuroprotection [
40]. BDNF has a critical role in some parts of the CNS, which regulate cognition, emotions, and reward activities [
41]. Numerous studies have indicated alterations in BDNF levels under neuropathological conditions. Specifically, METH use has been shown to significantly decrease BDNF levels through the reduction of CREB activities. Furthermore, disruption of normal AKT/GSk3 signaling pathways has been linked to METH use, which may contribute to the exacerbation of neurological and neurobehavioral symptoms [
40,
42,
43,
44]. Thus, in this investigation, we analyzed the overexpression of TNF-α and examined alterations in the CREB/BDNF and Akt-1/GSK3 signaling pathways in postmortem amygdala samples obtained from individuals with a history of METH addiction.