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How does methamphetamine (meth) damage neurons?

How does methamphetamine (meth) damage neurons?


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Meth is considered to be neurotoxic by forming reactive oxygen species and oxidizing the neurons. But unlike dopamine, which, by the way, is neurotoxic due to ROS induced dopaminergic stress, meth does not have any oxygen atom, and thus cannot be the direct cause of ROS.

So, how exactly does meth exert its neurotoxic effects?


Nice question! I will directly begin with the process through which methamphetamine causes damage to neurons, putting in as much details as are known, and adding appropriate citations wherever required.

Methamphetamine (METH) is known to act by increasing concentration of dopamine in brain1. When excess of dopamine is produced, it causes oxidative damage to axon terminals2. This is because direct oxidation of dopamine leading to quinone formation3, iron-catalyzed dopamine metabolism via Fenton reaction4, and metabolism of dopamine by monoamine oxidase-A5 contribute to production of superoxide and hydrogen peroxide.

Methamphetamine is known to increase concentration of glutamate. This (supposedly) happens as: high concentration of methamphetamine D1-mediated striatonigral GABAergic transmission, which in turn activates GABA-A receptors in substantia nigra pars reticulata (SNr), leading to increase in GABAergic nigro-thalamic activity which increases corticostriatal glutamate release6 (since I can't explain all those terms in a single answer). Now, excessive glutamate activates the glutamate-activated NMDA and AMPA receptors which, in turn, increases activity of nitric oxide synthase7. Activation of nitric oxide synthase generates reactive nitrogen species which create an oxidative stress8.

Oxidative stress is further increased because of depletion of antioxidant enzymes due to methamphetamine itself9. Now, the oxidative stress has to be manifested somehow. This is done by lipid peroxidation and protein carbonyl formation10, and also by specific nitration and nitrosylation of proteins important for monoamine synthesis and release, including VMAT-2 and tyrosine & tryptophan hydroxylase7,11,12. Oxidative modification of these proteins restricts their activity and contributes to their degradation, thus playing a major role in neurotoxicity. Researches substantiate the significant contribution of oxidative stress to the neurotoxicity of substituted amphetamines antioxidant treatments have also been shown to be neuroprotective against the damage produced by methamphetamine or methylenedioxymethamphetamine13,14,15.

P.S.: oxidative damage is not the only way through which methamphetamine causes neurotoxicity. Other possible ways include altered metabolism16, damage to mitochondria17, peripheral organ damage18 due to oxidative modification of hepatocellular mitochondrial proteins19, activation of microglia in striatum, cortex and hippocampus20, etc. Also, cannabinoids are known to suppress inflammatory processes and damage during methamphetamine exposure21. But since this is out-of-scope for this question, I won't go into their details.

References:

1. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Mol. Neurobiol. 51 (2): 696-717. doi:10.1007/s12035-014-8776-8. PMC 4359351Freely accessible. PMID 24939695.

2. Schmidt CJ, Ritter JK, Sonsalla PK, Hanson GR, Gibb JW. Role of dopamine in the neurotoxic effects of methamphetamine. The Journal of pharmacology and experimental therapeutics. 1985;233:539-544

3. Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Molecular pharmacology. 1978;14:633-643

4. Yamamoto BK, Zhu W. The effects of methamphetamine on the production of free radicals and oxidative stress. J Pharmacol Exp Ther. 1998;287:107-114

5. LaVoie MJ, Hastings TG. Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci. 1999;19:1484-1491

6. Mark K. A., Soghomonian J.-J., Yamamoto B. K., High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity. J. Neurosci. 24, 11449-11456 (2004)

7. Eyerman DJ, Yamamoto BK. A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine. J Neurochem. 2007;103:1219-1227

8. Imam SZ, Islam F, Itzhak Y, Slikker W, Jr, Ali SF. Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage. Annals of the New York Academy of Sciences. 2000;914:157-171

9. Jayanthi S, Ladenheim B, Cadet JL. Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice. Annals of the New York Academy of Sciences. 1998;844:92-102

10. Gluck MR, Moy LY, Jayatilleke E, Hogan KA, Manzino L, Sonsalla PK. Parallel increases in lipid and protein oxidative markers in several mouse brain regions after methamphetamine treatment. J Neurochem. 2001;79:152-160

11. Kuhn DM, Aretha CW, Geddes TJ. Peroxynitrite inactivation of tyrosine hydroxylase: mediation by sulfhydryl oxidation, not tyrosine nitration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999;19:10289-10294

12. Kuhn DM, Geddes TJ. Peroxynitrite inactivates tryptophan hydroxylase via sulfhydryl oxidation. Coincident nitration of enzyme tyrosyl residues has minimal impact on catalytic activity. The Journal of biological chemistry. 1999;274:29726-29732

13. Gudelsky GA. Effect of ascorbate and cysteine on the 3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin. J Neural Transm. 1996;103:1397-1404

14. Sanchez V, Camarero J, O'Shea E, Green AR, Colado MI. Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats. Neuropharmacology. 2003;44:449-461

15. Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M. Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain research. 2004;1016:90-95

16. Pontieri FE, Crane AM, Seiden LS, Kleven MS, Porrino LJ. Metabolic mapping of the effects of intravenous methamphetamine administration in freely moving rats. Psychopharmacology. 1990;102:175-182

17. Burrows KB, Gudelsky G, Yamamoto BK. Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration. European journal of pharmacology. 2000;398:11-18

18. Smith DE, Fischer CM. An analysis of 310 cases of acute high-dose methamphetamine toxicity in Haight-Ashbury. Clin Toxicol. 1970;3:117-124

19. Moon KH, Upreti VV, Yu LR, Lee IJ, Ye X, Eddington ND, Veenstra TD, Song BJ. Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver. Proteomics. 2008;8:3906-3918

20. Pubill D, Canudas AM, Pallas M, Camins A, Camarasa J, Escubedo E. Different glial response to methamphetamine- and methylenedioxymethamphetamine-induced neurotoxicity. Naunyn-Schmiedeberg's archives of pharmacology. 2003;367:490-499

21. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC neurology. 2006;6:12


Chapter Eight - The Pathology of Methamphetamine Use in the Human Brain

Information on brain pathology is important from a public health point of view and might also provide clues as to new targets for therapeutic intervention in the methamphetamine user.

The scope of the review is largely focused on questions whether methamphetamine, as suggested by experimental animal data, might change or damage brain neurons that use dopamine as a neurotransmitter and also cause changes in brain suggestive of neurotoxicity (oxidative stress, gliosis, decreased brain size).

The many confounds in human methamphetamine studies make conclusions on brain pathology difficult. There are many generic difficulties and confounds associated with studies of human methamphetamine users designed to establish whether the drug causes harm to the brain. These include lack of proof (e.g. by hair or repeated urine testing) in most investigations that drug users primarily or exclusively used methamphetamine and did not use other drugs that could cause brain pathology, and uncertainty whether changes present in brain were caused by methamphetamine or were a preexisting abnormality. Scatterplots of individual data are also not always provided making it impossible to establish whether brain differences in individual studies are robust.

In addition, there is a continuing uncertainty whether differences in levels of any of the brain biochemical markers of dopamine or other neurons possibly affected, can be equated with actual changes in neuronal integrity. In this regard, readers are cautioned to be skeptical of any conclusion in the methamphetamine literature that a change in a brain biochemical neuronal marker necessarily equals loss of part or all of a dopamine neuron.

To date, no brain pathology of chronic methamphetamine users has been reported that is a characteristic defining, or obligatory feature. Differences in a variety of brain markers in methamphetamine users have been described, but none can absolutely differentiate methamphetamine users from normal subjects, with levels of most markers showing overlap when comparing ranges of control and drug-user values.

Methamphetamine probably causes changes in levels of brain markers of dopamine neurons of some drug users, but it is not clear whether this represents neuronal loss or an otherwise pathological state. A variety of dopamine neuronal markers have been measured in postmortem and/or living brain of methamphetamine users, including dopamine, its metabolites homovanillic acid and dihydroxyphenylacetic acid, the dopamine biosynthetic enzymes tyrosine hydroxylase and dopa decarboxylase, the dopamine and vesicular monoamine (VMAT2) transporters, and several dopamine receptors. Three potentially meaningful findings have been reported:

The first finding, still awaiting replication, is low striatal (caudate, putamen, nucleus accumbens) concentrations of dopamine in autopsied brain of methamphetamine users, all who had recently used the drug. The magnitude of the reduction was near total in some subjects, with little overlap between control and drug user values in caudate, and suggests that high dose methamphetamine, a dopamine releaser, can cause massive release of the neurotransmitter such that tissue stores of dopamine are depleted. Low dopamine might explain some negative aspects of the methamphetamine abstinence syndrome.

A second dopamine-related finding is a reduction, typically of modest magnitude, of the striatal dopamine transporter, a change that probably normalizes to some extent in extended abstinence. The transporter difference is the most replicated finding in studies of dopamine markers in methamphetamine users. It has been reported in two postmortem brain investigations and in six independent imaging studies of living brain. It continues to be debated whether low transporter levels (reputedly lasting up to many years of abstinence in some investigations) has functional significance or is associated with loss of transporter-containing dopamine nerve endings.

The third observation is the lack, at present, of any marked reduction in striatal levels of some other dopamine neuronal markers, including dopamine metabolites, dopa decarboxylase, and VMAT2, as occurs in Parkinson’s disease.

Other dopaminerigic changes reported in brain imaging studies include slightly decreased striatal binding to the dopamine D2 receptor, and a preliminary finding of increased binding to the dopamine D3 receptor—differences that might relate to aspects of addiction to methamphetamine, although this link is not yet established.

Changes in nondopaminergic markers. These differences include a reduction in biochemical markers of serotonin neurons (generally consistent with animal findings) and decreased striatal concentration of the neuropeptide met-enkephalin—findings consistent with either loss of serotonin and met-enkephalin-containing neurons, or neuroadaptation without neuronal loss.

Does methamphetamine cause brain oxidative stress? Animal data suggest that methamphetamine might cause oxidative brain damage, with dopamine-rich brain areas showing higher oxidative stress. Results of a postmortem brain study of methamphetamine users, awaiting replication, support this possibility, with a finding of markedly elevated concentrations of two lipoperoxidation products, 4-hydroxynonenal and malondialdehyde. Changes were most marked in the dopamine-rich striatum and related to drug dose.

Studies of brain gliosis of methamphetamine users: Findings are intriguing but no clear picture yet emerges. Microglial activation and reactive astrogliosis are common features of neurotoxic insult. Information on brain gliosis is primarily limited to two methamphetamine investigations: a postmortem investigation in drug users (who had very recently used methamphetamine) reporting increased number of microglial cells in striatum but no increase in activated microgliosis, and a brain imaging study, employing a putative marker of activated microglial cells, showing high binding to the marker throughout the brain of methamphetamine users, withdrawn for up to 2 years after a last drug use. The two gliosis findings are still too preliminary, difficult to reconcile, and (the imaging study) uncertain because of the first generation radiolabelled probe employed, but the question remains whether methamphetamine might induce a progressive, persistent brain neurodegeneration accompanied by gliosis in some subjects.

Is methamphetamine exposure associated with smaller or larger brain size? Structural imaging investigations generally suggest slightly lower cerebral cortical gray matter density and striatal enlargement (related to gliosis?) in some drug users. However, the findings are not yet definitive or, in the case of the striatal difference, consistent, and the influence of abstinence time and use of other recreational drugs on the outcome measures remains to be resolved.

Increased risk of Parkinson’s disease in methamphetamine users? A large longitudinal population-based cohort investigation employing inpatient hospital databases from California reports increased risk of subsequent development of Parkinson’s disease in methamphetamine users. This is a preliminary finding, requiring replication, and is associated with many confounds however, the study does suggest that high dose use of methamphetamine might increase risk of developing Parkinson’s disease in later life.

Major Conclusions. There is as yet no characteristic or defining brain pathology of chronic methamphetamine users, with the exception of the still undiscovered pathology responsible for compulsive drug taking in the subgroup of chronic methamphetamine users who are addicted to the drug.

Regarding brain dopamine-related changes, the reported differences that most impress this reviewer are the striatal dopamine depletion associated with acute drug use, because of the striking magnitude of the change and minimal overlap between drug user and control values, and the striatal dopamine transporter reduction, because of the many replications of the finding in the postmortem brain and brain imaging literature. A severe striatal dopamine transporter reduction (below control levels) is unlikely to be a feature of all methamphetamine users, but future studies of representative numbers of drug users are likely to continue to find a modest mean group reduction in comparison with control values. The lack, to date, of any substantial reduction in other dopamine markers (dopamine metabolites, VMAT2) suggests that if there is any loss of dopamine nerve terminals in methamphetamine users, the extent of loss is probably only typically slight.

At present, a statement that methamphetamine causes physical-structural (vs adaptive-neurochemical) damage to dopamine neurons in the human is not justified.

In terms of measures that might be related to physical damage to brain neurons, the postmortem brain finding of increased levels of oxidative stress indices is noteworthy because of the large magnitude of the change and association with extent of dopaminergic innervation and drug dose. The glial and structural brain changes in methamphetamine users are both highly provocative but still early, not yet definitive findings, with more work needing to be done to confirm the extent to which these changes occur and are related specifically to methamphetamine use. Glial changes assumed to occur from brain imaging studies must be confirmed by histopathological analysis in postmortem brain. A statement that methamphetamine causes “holes in the brain” is at present unjustified.


Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling

Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH-pretreated animals and the 6-hydroxydopamine model of Parkinson's disease suggests that a disruption of phasic DA signaling, which is important for learning and goal-directed behavior, may be such a link. However, previous studies used electrical stimulation to elicit phasic-like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH-induced DA terminal loss on both electrically evoked phasic-like DA signals and so-called 'spontaneous' phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these subsecond DA changes may play a role in enhancing reward-cue associations. METH pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by

55%. Analysis of phasic-like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH-induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH-induced striatal DA depletions and cognitive deficits.

Keywords: psychostimulant rat striatum transient voltammetry.

© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Figures

Figure 1. Experimental design and analyses

Figure 1. Experimental design and analyses

Recording locations were estimated from stereotaxic coordinates and top…

Figure 2. Effects of METH neurotoxicity on…

Figure 2. Effects of METH neurotoxicity on evoked phasic-like DA signals

Representative evoked phasic-like DA…

Figure. 3. Effects of METH neurotoxicity on…

Figure. 3. Effects of METH neurotoxicity on DA innervation and characteristics of phasic-like DA responses…

Figure 4. Effects of METH neurotoxicity on…

Figure 4. Effects of METH neurotoxicity on spontaneous DA transients

Representative recordings show spontaneous phasic…

Figure 5. Effects of METH neurotoxicity on…

Figure 5. Effects of METH neurotoxicity on characteristics of DA transients

Figure 6. Analysis of the interaction between…

Figure 6. Analysis of the interaction between reinforcing electrical stimulation and DA transients


METH neurotoxicity and reactive gliosis

For a variety of reasons methamphetamine’s neurotoxic effects, although well-studied, are not well-defined [6]. In experimental studies, variations of METH doses, routes of administration, duration of METH exposure, and species specificity have collectively confounded the interpretation of the neurotoxic effects of METH and therefore their pathophysiological significance for humans (Fig. 1). Multiple mechanisms are thought to mediate METH-induced neurotoxicity: increase in neuronal firing rate, increased concentrations of intracellular Ca + 2 and Na + ions, dysregulation of mitochondrial function, neuronal energetic imbalance, and overproduction of reactive oxygen species. The primary goal of the current review is to re-evaluate this neurotoxicity from the perspective of reactive microglial cell changes, as neuroinflammatory reactions have been reported to occur following METH administration and are believed to causally contribute to METH-induced neurotoxicity [5,6,7].

Immunohistochemical staining of Iba1 antigen for visualizing mouse microglial cells after METH administration. 3D reconstructions of 60× stacked images of microglia from striatum, CA1 and dentate gyrus of hippocampus, and from amygdala after 7 days of single, daily i.p. injections of either saline or METH (4 mg/kg). Note the absence of microglial hypertrophy (activation) after METH suggesting minimal neurotoxic damage in this particular injection paradigm. Graticule size, 20 μm

Rather than viewing microglia as potentially harmful cells that attack neurons, we view microglia as sensitive biological indicators of neuronal perturbations and perhaps the most reliable cellular sentinels of neurotoxic effects and neuronal damage in general. Microglia have long been recognized as “sensors of pathology” [8] because they are continuously monitoring neuronal well-being and become alerted (activated) when neuronal activity is disturbed or compromised by injury, disease, or neurotoxic agents. There is a regular and bidirectional crosstalk between microglia and dopamine neurons involving diverse receptors and ligands, including both D1-like and D2-like dopamine receptors [9]. Therefore, increased or decreased extracellular dopamine levels are predicted to affect the biology of microglial cells and dopamine neurons in a bidirectional manner. As the brain’s immune system, one of the prime functions of microglia is to be the first line of defense and engage in neuroprotection whenever necessary [10, 11]. To this end, microglia need to sense which neuronal perturbations require their attention and intervention.

We understand the term “neurotoxicity” to mean that METH exposure is directly toxic to neurons, but not necessarily in the sense that METH kills neurons. Dopaminergic neurons are of particular interest because METH is known to directly target dopamine neurons it competes with the uptake of released dopamine via the dopamine transporter (DAT) it disrupts vesicular storage of dopamine and induces reverse transport of dopamine through the transporter termed “dopamine efflux” [12,13,14,15]. These actions of METH result in extracellular dopamine concentrations remaining elevated while METH is present, but it is still being debated whether or not elevated dopamine itself is neurotoxic. Neurotoxicity is indicated by the sequelae of METH exposure, which include degeneration of axon terminals in the striatum, as shown by silver cupric impregnation [16, 17], neurochemical changes, such as decreased tyrosine hydroxylase (TH) and DAT levels, depletion of dopamine and its metabolites [16, 18,19,20], as well as reactive astrogliosis [16] and microgliosis (next paragraph). Reactive astrogliosis (astrocytic scarring) typically follows an initial response by microglial cells. Robust and persistent increases in the astroglial intermediate filament protein, GFAP, have been measured [21], but increased GFAP levels allow no more than a general conclusion that sustained astroglial scarring has occurred due to some (unspecified) neuronal damage. Measurements of GFAP expression do not allow conclusions about whether or not neuronal death has occurred acutely. Neuronal death is the most severe consequence of neurotoxicity and the primary cause for neuronal loss.

Microglial reactions visualized histopathologically are more telling than biochemical measures of GFAP in that the microscopic observation of microglial responses better inform about the regional specificity, nature, and severity of METH-induced neurotoxicity. Not only do microglia display different morphological forms after a damaging event, their surface immunophenotype is marked by presence of multiple membrane-bound receptors that undergo characteristic changes during activation, which are detectable with antibodies directed against a variety of immunological important molecules, such as major histocompatibility (MHC) antigens, complement and Fc receptors, integrins, surface immunoglobulins, and toll-like receptors, in addition to presence of intracellular microglial antigens, like the ionized calcium-binding adapter molecule 1 recognized by the Iba1 antibody [22]. Nevertheless, these immunophenotypical and microanatomical changes are neither global nor universal amongst different species and can vary substantially in accordance with lesion severity thus allowing refined assessments of pathology.


Can cognitive impairments caused by methamphetamine use perpetuate the addiction cycle?

Methamphetamine, also known as meth, is a highly addictive stimulant that first surfaced in the 20th century and has since become one of the most abused substances worldwide. The U.S. Drug Enforcement Administration classifies methamphetamine as a Schedule II stimulant, which means that it can only be legally purchased with a nonrefillable prescription. While it is sometimes prescribed in low doses to treat attention deficit hyperactivity disorder (ADHD) or a few other health conditions, the sense of euphoria it typically elicits has resulted in many people becoming addicted to it and purchasing it illegally for recreational use.

Methamphetamine addiction is a highly detrimental substance use disorder that is often associated with a wide range of psychiatric symptoms, cognitive impairments, and a severe risk of relapse after treatment. Past studies suggest that regular meth consumption can adversely affect a number of cognitive domains, including a user’s attention, impulsivity, and memory. However, the relationship between meth-related cognitive impairments, addiction, and relapse is still poorly understood.

Dr Carmela Reichel, Associate Professor at the Medical University of South Carolina, has been conducting research investigating the cognitive and neural underpinnings of meth addiction, as well as other substance use disorders, for several years. Her research is helping to identify impairments caused by repeated meth use that could perpetuate the addiction cycle and increase the risk of relapse in regular users.

Regular meth consumption can adversely affect a number of cognitive domains, including a user’s attention, impulsivity, and memory.

The effects of regular meth use on attention, memory, and impulse control
Past research in the fields of neuroscience and psychology has repeatedly highlighted the adverse effects that continuous meth intake can have on specific brain regions and the cognitive functions associated with these regions. The most pronounced and enduring effects of repeated meth use are on the brain’s executive functions, which include a variety of cognitions associated with decision-making, attentional control, and working memory. Additionally, past findings suggest that meth consumption can impair people’s ability to recall events planned or in the past of their life (i.e. their procedural and episodic memory) and to mentally process information. All of these cognitive functions are typically associated with activity in cortical and subcortical brain structures, which appear to undergo significant maladaptive changes as a result of continuous meth consumption.

A brain region that appears to be compromised after meth use is the perirhinal cortex (PRH), which is an important neural substrate that allows people to recognise things that they observed in the past (i.e. recognition memory), while also directing the flow of information into and out of the parahippocampal structure. Other structures that are impacted by repeated meth use are the medial prefrontal cortex (mPFC), which is known to mediate inhibitory control over risky behaviours (e.g. drug overconsumption), and the nucleus accumbens core (NAcore), an area that regulates reward-related behaviours.

Brain regions that seem to be compromised after meth use are the the prefrontal cortex, the nucleus accumbens core and the perirhinal cortex. Damages to these regions result in memory impairment, loss of impulse control and bias to drug-related stimuli.

Brain regions that seem to be compromised after meth use are the the prefrontal cortex, the nucleus accumbens core and the perirhinal cortex. Damages to these regions result in memory impairment, loss of impulse control and bias to drug-related stimuli.

Combined, damage to these brain regions results in significant memory impairments, a loss of control over impulses, and a bias to drug-related stimuli (e.g. objects associated with meth consumption) that might make addicts more prone to relapse.

Meth-induced memory deficits could fuel the addiction cycle
Dr Reichel has carried out a number of studies investigating the effects that repeated meth use can have on memory and ways to restore those memory processes affected by meth. In addition, she explored the possible links between these effects and the high risk of relapse associated with meth addiction, which could ultimately help to devise more effective treatments for meth use disorders.

With her work, Dr Reichel hopes to reduce the risk of relapse among individuals who are addicted to meth.

In her studies, Dr Reichel observed that repeated meth intake can dysregulate the PRH, which is involved in recognition memory. She thus hypothesised that meth addicts sometimes struggle with recognition memory due to a loss of communication between PRH projection neurons and the mPFC. Moreover, she proposed that the neural pathway containing prelimbic (PL) outputs of the mPFC that project to the NAcore region is adversely affected by meth use, which increases the relevance of drug-related cues, leading to high relapse rates.

Distinct pathways seem to mediate the characteristic impairments in object recognition (PRH-mPFC) and the high risk of relapse (PL-NAcore) seen in meth use disorder. While the PRH-mPFC neural pathway has been the focus of numerous research studies, the effects of the PRH-NAcore pathway on behaviour are still poorly understood. Dr Reichel suggests that this pathway could be the link between meth-induced memory impairments and relapse.

Reversing memory deficits to reduce the risk of relapse
After identifying meth-induced brain alterations and cognitive impairments that could perpetuate the addiction cycle, Dr Reichel started investigating interventions that could reverse the meth-induced damage in recognition memory and thus potentially help to reduce the risk of relapse.

Dr Reichel’s experiments on male and female rats showed that the long-term consumption of meth led to both sexes failing to recognise novel objects. She observed that this inability to recognise objects was associated with a long-term reduction of activity or depression in the PRH cortex.

Subsequently, Dr Reichel found that modulating mGluR5 (metabotropic Glutamate receptor 5) in the PRH cortex could partially reverse the adverse effects of meth use on the rats’ ability to recognise new objects and a bias towards meth-related stimuli.

Dr Reichel is investigating interventions that could reverse the meth-induced cognitive impairments to prevent relapse and thus break the addiction cycle.

By infusing a new positive allosteric mGluR5 modulator, called 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, into the PRH cortex of rats who had repeatedly used methamphetamine for an extended period of time, Dr Reichel and her colleagues were able to restore novelty salience. This essentially means that after these infusions, the rats responded in the same way to new and meth-related stimuli, while they previously responded to the latter with meth-seeking behaviour. These findings suggest that targeting mGluR5 receptors in the PRH cortex could potentially be a promising strategy for reducing the risk of relapse in meth addicts.

In one of her most recent works, Dr Reichel conducted a different experiment to test the hypothesis that meth-induced novel object recognition deficits (associated with depression in the PRH cortex) increase the vulnerability of individuals who are addicted to meth to relapse. Here, she tried to restore the rats’ novel object recognition memory by applying an excitatory Gq-DREADD (a synthesised receptor) on perirhinal neurons. Designer receptors exclusively activated by designer drugs (DREADDs) are essentially artificially created receptors that allow neuroscientists to selectively intervene on neural pathways with high precision in order to investigate the functions and behaviours associated with different brain regions or neuron populations.

Dr Reichel started investigating interventions that could reverse the damage to meth users’ recognition memory and thus potentially help to reduce the risk of relapse.

The Gq-DREADD-based intervention carried out by Dr Reichel and her colleagues appeared to confirm their hypothesis. In fact, they found that the use of these synthesised receptors to activate perirhinal neurons reversed meth-induced novel object recognition deficits and restored novelty salience, in a similar way to their previous experiment that targeted mGluR5 receptors.

Moving towards more effective treatments for meth addiction
Dr Reichel’s research offers valuable new insight that could help to devise more effective strategies to treat methamphetamine use disorder. In addition to confirming the adverse effect of long-term and repeated meth use on the PRH-mPFC and PL-NAcore neural pathways, as well as the associated repercussions on individual users’ memory, attention, and impulse control, her work shows that some of these deficits could fuel patterns of addiction and make meth addicts more prone to relapse.

Notably, Dr Reichel found that some memory impairments associated with meth use could be partly overturned using chemogenetic techniques. More specifically, she observed that interventions targeting mGluR5 and GluN2b receptors in the PRH cortex or enhancing signalling of perirhinal neurons could reverse adverse effects on meth addicts’ novel object recognition memory, thus reducing their bias towards meth-related stimuli and increasing their willingness to respond to new stimuli that they do not associate with meth use.

In the future, the findings gathered by Dr Reichel and her colleagues could inform the development of new pharmacological treatments and chemogenetic interventions that could reduce the risk of relapse among individuals who are addicted to meth. By targeting glutamate receptors or neurons in the PRH cortex, these treatments could also help to restore some of the patients’ memory functions, helping them on their path to recovery.

Personal Response

What inspired you to conduct this research?

Addiction is a debilitating disorder that effects individuals, families, and communities. I am passionate to help discover ways to alleviate the distress involved with addiction by finding ways to help maintain abstinence from drugs. Addiction is a complex cyclic disorder and to overcome the cycle, interventions must occur to break it. To break the cycle, researchers need a comprehensive understanding of the cognitive, behavioural, and neural systems that are disrupted in addiction pathology. Contributing to help find the solutions of addiction inspires me to conduct this research.


Effects of DDIT4 in Methamphetamine-Induced Autophagy and Apoptosis in Dopaminergic Neurons

Methamphetamine (METH) is an illicit psychoactive drug that can cause a variety of detrimental effects to the nervous system, especially dopaminergic pathways. We hypothesized that DNA damage-inducible transcript 4 (DDIT4) is involved in METH-induced dopaminergic neuronal autophagy and apoptosis. To test the hypothesis, we determined changes of DDIT4 protein expression and the level of autophagy in rat catecholaminergic PC12 cells and human dopaminergic SH-SY5Y cells, and in the hippocampus, prefrontal cortex, and striatum of Sprague Dawley rats exposed to METH. We also examined the effects of silencing DDIT4 expression on METH-induced dopaminergic neuronal autophagy using fluorescence microscopy and electron microscopy. Flow cytometry and Western blot were used to determine apoptosis and the expression of apoptotic markers (cleaved caspase-3 and cleaved PARP) after blocking DDIT4 expression in PC12 cells and SH-SY5Y cells with synthetic siRNA, as well as in the striatum of rats by injecting LV-shDDIT4 lentivirus using a stereotaxic positioning system. Our results showed that METH exposure increased DDIT4 expression that was accompanied with increased autophagy and apoptosis in PC12 cells (3 mM) and SH-SY5Y cells (2 mM), and in the hippocampus, prefrontal cortex, and striatum of rats. Inhibition of DDIT4 expression reduced METH-induced autophagy and apoptosis in vitro and in vivo. However, DDIT4-related effects were not observed at a low concentration of METH (1 μM). These results suggest that DDIT4 plays an essential role in METH-induced dopaminergic neuronal autophagy and apoptosis at higher doses and may be a potential gene target for therapeutics in high-dose METH-induced neurotoxicity.

Keywords: Apoptosis Autophagy DNA damage-inducible transcript 4 (DDIT4) Dopamine Methamphetamine Neurotoxicity.


Meth Demons: How methamphetamine addicts develop parasitic fungal infections

This article details the science of how Methamphetamine (METH) addiction has been proven to cause serious fungal infections in users. These fungal infections that addicts develop that I contend are the main reason they engage in socially and morally unacceptable behavior and develop mental illness, which culminates into suicidal tendencies and nihilistic world views.

Often, just in a few short years, they go from looking like normal people to what we can call a demon-like appearance and behaviors. Hence, it makes them Meth Demons who seem to be hell-bent on destroying themselves and everyone around them.

My theory is that it is not just the METH that makes addicts crazy, but it is the fungi/molds that grow within their lungs and gastrointestinal tracts, which has been proven to be our second brain. Various studies have shown how quickly this weakens their immune system from ingesting a drug containing things like battery acid, fuels, antifreeze, and cold medicines combined with horrible eating habits, a severe deficiency of vitamins, a lack of sun, and a lack of sleep.

When you combine all these toxic ingredients with terrible health habits into a daily routine, studies show that METH addicts quickly develop serious fungal infections, and I believe it is these organisms that have turned parasitic within addicts that are manipulating them and controlling their actions via this second brain.

In my experience, these addicts are humans. Many are good people who may be our sons and daughters who have ignorantly partaken in a deadly drug that can cause a severe medical condition that can destroy their health and steal their personalities and ultimately ruin their lives.

Who would tolerate and still use a drug like METH that destroys how we look, our relationships, how we think, feel, and act and eventually lead to our death?

Are the people who use these drugs still “in control of their bodies and minds” or is their drug use resulting in a “pathogen” that is hell-bent on mind-controlling their victims?

Before I began sharing my research, I would like you to think about some questions that I believe will give you context to my theory as you read further

* Did you know that chronic METH use severely increases the chances of a systemic fungal infection in the lungs and brains of users?

* Did you know that both METH and molds/fungi cause biochemical, behavioral, and physiological abnormalities and psychosis?

* Did you know that both METH and molds/fungi can lead to long-term deterioration of attention, memory, and judgment?

* Did you know that both METH addicts and molds/fungi love sugar?

HOW METHAMPHETAMINE USE CAUSES SYSTEMIC FUNGAL INFECTIONS

In the United States of America, Methamphetamine (METH) addiction is one of the worst threats to our society because it adversely changes people’s behavior, making them more prone to crime and carriers of and transporters of various infectious diseases. One of these diseases that METH addicts are highly susceptible to developing and influencing their pathogenic behavior that I would like to bring to your attention is a systemic fungal infection.

It is essential to understand that METH use destroys your immune system and make addicts much more susceptible to infection. Several studies have been done over the last decade, showing the severe impact of methamphetamine on infection and immunity. A 2015 study had shown that as a result of drug use, our bodies create chemical defenses, which increases the pro-inflammatory responses, and the induction of oxidative stress pathways.

This causes significant neurotoxicities to arise, increasing the risk for acquiring transmissible microbes and other opportunistic infections such as systemic fungal infections this research has been documented worldwide (Plankey et al., 2007 Volkow et al., 2007 Ye et al., 2008 Sutcliffe et al., 2009 Parry et al., 2011 Borders et al., 2013 Eugenin et al., 2013 Heninger and Collins, 2013 Khan et al., 2013 Stahlman et al., 2013 Liao et al., 2014).

According to the researchers in the study

METH abrogates normal macrophage function, resulting in accelerated disease in murine histoplasmosis (Martinez et al., 2009). METH decreases phagocytosis and killing of H. capsulatum by primary macrophages. METH exposed H. capsulatum-infected mice have increased fungal burdens, increased pulmonary inflammation, and reduced survival.

METH exposure results in cytokine dysregulation, aberrant processing of yeasts within macrophages, and immobilization of MAC-1 receptors on the macrophage surface. Additionally, METH inhibits T cell proliferation and alters antibody production, both important components of adaptive immunity. Hence, it is established that METH alters the immune system of a mammalian host, resulting in enhanced disease (Martinez et al., 2009). (1)

It has been proven by science through various studies that METH has diverse effects on a person’s immunity, and it also stimulates fungal adhesion and biofilm formation in the lungs, which causes dissemination of the fungus from the respiratory tract into the brain. Meaning it provides the perfect environment in your body for molds/fungi to grow, reproduce, and become permanent residents in our lungs and brain.

This is when I believe the fungi become pathogenic and can seriously manipulate an addict’s mind to do its bidding like they have been proven to do in other insects.

It turns humans into walking and talking fungal parasites – AKA Demons!

To document these transformations in their appearance and in hopes to scare other people from using this demon drug, the Faces of Meth campaign was launched in 2004. Their goal was to show before and after pictures of users side by side, which proves the devastation that meth use causes to addicts – sometimes over the course of a few months.

According to a study done in 2013, researchers discovered that METH use has profound implications on tissue homeostasis and the host’s capacity to respond to invading pathogens such as Cryptococcus neoformans (C. neoformans). (2) Meaning, that people who use METH are weakened to the point that they do not have a healthy immune system which allows pathogens such as the microorganism known as fungi or molds in English that causes, or can cause, disease and damage in its host.

The researchers call this an “enhanced fungal invasion.”

According to the lead researcher, Luis Martinez of Long Island University-Post, in Brookville, New York and of Albert Einstein College of Medicine in The Bronx

Martinez says this greater ability to cause disease in the lung may be due in part to simple electrical attraction.

Their analysis shows that METH imparts a greater negative charge on the surface of the fungal cells, possibly lending them a greater attraction to the surface of the lung and an enhanced ability to form a biofilm that can protect its members from attack by the immune system. The fungus also releases more of its capsular polysaccharide in METH-treated mice, which can help the organism colonize and persist in the lung.

He commented, “When the organism senses the drug, it basically modifies the polysaccharide in the capsule. This might be an explanation for the pathogenicity of the organism in the presence of the drug, but it also tells you how the organism senses the environment and that it will modify the way that it causes disease.”

But the fungus doesn’t stop in the lungs. “The drug stimulates colonization and biofilm formation in the lungs of these animals,” says Martinez. “And this will follow to dissemination to the central nervous system by the fungus,” Martinez says.

The conclusion of the study stated

“METH promotes C. neoformans colonization of the lungs upon infection and subsequent biofilm formation. Our findings suggest that C. neoformans biofilms may act as a fungal reservoir, shielding single cells from phagocytic cells, which can later disseminate, especially to the CNS. Moreover, the drug causes profound defects in the integrity of the Blood-Brain-Barrier BBB in vivo, increasing permeability, and facilitating the transmigration of C. neoformans to the CNS.

METH-induced alterations to the molecules responsible for maintaining the integrity of the BBB provide an explanation for the susceptibility of a METH abuser to brain infection by HIV and other pathogens. Broadly, METH has diverse and pronounced detrimental effects on host immunity that can also enhance pathogen persistence and proliferation.”

I would like to point out that METH is a drug that acts upon the central nervous system and chronic meth abuse causes detrimental effects on host immunity, which can lead to the fungi/molds proliferating the lungs and the blood brain barrier through the central nervous system.

It is akin to the fungi taking a bullet train to your brain via the central nervous system.

In some people, the parasite-host manipulation from the GI Tract can start happening immediately or within days/weeks causing them to develop psychosis or go insane i.e.: parasite-controlled humans.

METH also causes the massive release of the neurotransmitters like dopamine, norepinephrine, and serotonin, and blocks their reuptake, leading to long-term deterioration of attention, memory, and judgment. (Downes and Whyte, 2005 Collins et al., 2014). That may be one reason why users make such poor choices repeatedly because they have forgotten how to be human, and the moral codes that govern our societies are swapped by the moral codes of the fungal parasite, of which there seem to be none.

Hence, you will know them by their fruits or, more appropriately, their moldy and decaying fruits.

Along with neuropsychiatric deficits, methamphetamine abusers suffer from mental illnesses such as anxiety, depression, and psychosis being the most commonly reported.

Now, let me turn your attention to the fact that the toxins produced by some fungi/molds are neurotoxins that are poisonous or destructive to brain and nerve tissue, which causes a condition known as neurotoxicity. The term neurotoxicity refers to damage to the brain or peripheral nervous system caused by exposure to toxins and myconeurotoxicity when a person is exposed to mold toxins, which I believe is exactly happening.

When mold mycotoxins cause neurotoxicity, it is called myconeurotoxicity, which refers to any adverse effects of exposure to mycotoxins or byproducts of primary and secondary mold metabolism, including volatile organic compounds (VOCs) on the structural or functional integrity of the developing or adult nervous system. Neuromycotoxic effects may involve a spectrum of biochemical, morphological, behavioral, and physiological abnormalities whose onset can vary from immediate to delayed actions, following exposure to mycotoxins. The duration of effects may be transient or persistent and result in disability in some individuals, while some may have life-threatening consequences. (3)

A November 2015 study of mice titled “Mold inhalation, brain inflammation, and behavioral dysfunction” was developed by researchers to show a mouse model to determine how mold exposure can lead to neurobehavioral dysfunction. The researchers had formed a hypothesis that mold inhalation, like a bacterial infection, activates an innate immune response triggering microglial activation with resultant behavioral dysfunction.

Here is an excerpt from the study:

“Deficits in contextual memory were correlated with numbers of amoeboid microglia and microglial size in the dorsomedial dentate gyrus. Spore inhalation increased the numbers of cells in the hippocampus expressing the proinflammatory cytokine interleukin-1beta (IL-1beta). Increased numbers of cells expressing IL-1beta in hippocampal CA1 were positively correlated with spatial memory deficits and increased fear.

Mold exposure also affected two of the three stages of neurogenesis. Inhalation of EX spores decreased numbers of immature new neurons in the dorsomedial hippocampus expressing doublecortin, while IN treatment decreased numbers of adult-born BrdU-labeled neurons that matured and expressed NeuN. Our data suggest that respiratory exposure to any mold, not just the particularly toxic ones like Stachybotrys, may be capable of causing brain inflammation, cognitive deficits, and emotional problems.” (4)

Immune system disorders and abnormal natural killer cell (NKC) activity was found in patients with chronic toxigenic mold exposure in a 2003 study. The major symptoms reported were headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures.

The researchers found that the patient’s sleep could be disturbed by mycotoxins and exerted some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity.

The researchers concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures.

This research correlates with other studies that have focused on mold exposure, brain changes, and neuropsychological problems such as mild traumatic brain injury, dysregulation of emotions, decreased cognitive functioning, short-term memory loss, executive function/judgment, concentration, and hand/eye coordination.

It is important that you understand my theory that it is not the methamphetamine that is causing the mental illness and psychosis, but that it weakens the users’ immune system, leading to a systemic fungal infection, additional infections. For example, it is not just the fungus, Cryptococcus neoformans (C. neoformans) that people need to worry about but other fungi can cause infection, illness, disease, and death in addicts.

METH CAUSES CANDIDA INFECTIONS AND CANDIDA INFECTION CAUSE MENTAL ILLNESS, ITCHING SYSTEMS, AND MEMORY LOSS

Candidemia, a bloodstream infection caused by Candida species and is prevalent amongst IV Drug users of METH. Candidemia is typically considered a health care-associated infection, but injection drug use (IDU) has emerged as an increasingly common condition related to candidemia. Among 203 candidemia cases in the Denver metropolitan area during May 2017–September 2018, 11% of the cases were IV drug users and of which 73% reported using METH, according to research published by the CDC. (5)

Studies have shown that METH facilitates intracellular replication and inhibits intracellular killing of Candida albicans and Cryptococcus neoformans. (6)

Candida is a yeast-like fungus naturally found in small amounts in human digestive tracts, but drugs enhance its overgrowth like METH with its chronic use, poor diet, excess sugar intake, and lack of sleep. Users often report itching sensations and scratch their skin, creating sores sometimes all over their bodies and faces. Users have even made claims of bugs, worms, and or flies crawling underneath their skin.

What is interesting is that Candida infections cause burning, itching symptoms, thrush (rashes in the throat or mouth), and sexually transmittable genital yeast infections in men and women.

Candida infections are linked to mental illness and are more common among those with memory loss.

The same mental issues that chronic Meth users suffer from.

For example, in a 2016 study published in Science Daily, both men and women with schizophrenia or bipolar disorder who tested positive for Candida performed worse on a standard memory test than people with the same disorders who had no evidence of past infection. According to the lead researcher, Emily Severance, Ph.D., assistant professor of pediatrics and member of the Stanley Division of Developmental Neurovirology at the Johns Hopkins University School of Medicine

“Although we cannot demonstrate a direct link between Candida infection and physiological brain processes, our data show that some factor associated with Candida infection, and possibly the organism itself, plays a role in affecting the memory of women with schizophrenia and bipolar disorder, and this is an avenue that needs to be further explored,” says Severance.

“Because Candida is a natural component of the human body microbiome, yeast overgrowth or infection in the digestive tract, for example, may disrupt the gut-brain axis.

This disruption, in conjunction with an abnormally functioning immune system, could collectively disturb those brain processes that are important for memory.

“However, most Candida infections can be treated in their early stages, and clinicians should make it a point to look out for these infections in their patients with mental illness.” She adds that Candida infections can also be prevented by decreased sugar intake and other dietary modifications, avoidance of unnecessary antibiotics, and improvement of hygiene. (7)


Methamphetamine

Methamphetamine is dangerous for many reasons however, one of the most damaging effects of meth is on the brain, specifically, on neurons and neurotransmitters. This consequently alters the efficiency of the rest of the nervous system, further damaging the body. This page is dedicated to exploring the specific biological chemicals that are effected by meth and how the regular fuctions of the body are changed by the presence of the drug in the nervous system.

In a normal nervous system, electrical signals are received and sent through the use of cells called neurons. The arrival of the signal at the end of the neuron triggers the release of chemicals, specifically neurotransmitters, into a gap between the end of one neuron (presynaptic) and the beginning of the next neuron (postsynaptic). This gap is called the synapse (Brooker, 2011). Neurotransmitters are released into the synapse and then bind to receptors located on the post-synaptic neuron (ibid). The binding of the neurotransmitter to the receptor triggers a response in the neuron. After this, the neurotransmitters left in the synapse are reabsorbed by the pre-synaptic neuron. This stops the post-synaptic neuron from being further triggered (ibid).

When methamphetamine is introduced to the nervous system, neurotransmitters are unable to be reabsorbed into the pre-synaptic neuron. This is because meth blocks the passages through which the chemicals are taken up through. This causes neurotransmitters to flood the synapse and continually trigger responses in the post-synaptic neuron. Meth affects 4 neurotransmitters in specific: dopamine, serotonin, epinephrine, and norepinephrine (Limpy, 1999).

Dopamine is the neurotransmitter responsible for feelings of pleasure, pain, and several other emotional responses (Erickson, 2012). A greater amount of the chemical causes sensations of pleasure and happiness, while a smaller concentration can have the opposite effect, causing the individual to feel pained or saddened. Dopamine is also responsible for movement (ibid). Too much dopamine can cause the individual to experience uncontrollable, repetitive movements and twitching, as often seen in meth addicts. Too little prevents movement, as in the cause of those with Parkinson’s disease. An increased amount of dopamine can also trigger bizarre hallucinations and delusions, causing the user to display similar psychological characteristics as individuals with schizophrenia. For example, meth users claim to see “bugs” beneath their skin, leading them to scratch and tear and their skin (Meth Project, 2012).

Methamphetamines not only block the reuptake of dopamine into the pre-synaptic cleft, but also cause the neurons to secrete more dopamine than normal – causing the synapse to become extremely flooded with the neurotransmitter. This flooding continually triggers the post-synaptic neuron, which creates the high sensation that users experience (Limpy, 2011).

Because meth causes dopamine to be secreted from the neurons, the amount of dopamine available is depleted significantly, and eventually drops below the necessary amount once the user begins to experience a crash. This causes the individual to have difficulty moving and display drastic mood swings (Meth Project, 2012).

Serotonin is the neurotransmitter responsible for sleep, appetite, mood, aggressive behavior, and sexual desire . An increase in serotonin allows for the individual to be less tired, less hungry, and more aggressive. High amounts of serotonin also heightens libido (news-medical.net). These characteristics can be observed in those who use methamphetamine, as such users display less tiredness and decreased appetite. This causes extreme weight loss in users and allows them to remain awake for long periods of time. Other characteristics include an increase in aggressive behavior and sexual desire (Limpy, 1999).

The presence of meth on serotonin, like dopamine, blocks the reuptake of the neurotransmitter – flooding the synapse. However, unlike dopamine, meth does not cause serotonin to be secreted by neurons into the synapse. Eventually, once the user begins to crash, the amount of serotonin drops below average, causing tiredness, hunger, and mood fluctuations(Meth Project, 2012).

Epinephrine

Epinephrine is more commonly known as adrenaline and has the ability to increase heart rate, blood pressure, as well as to dilate air passages. Epinephrine is also responsible for ‘fight-or-flight’ response (Limpy, 1999).

Like in serotonin, meth blocks the reuptake of epinephrine into the pre-synaptic cleft, causing the user to experience a faster heart rate and blood pressure (Meth Project, 2012). This can eventually lead to devastating effects on the cardiovascular system (see Cardiovascular System).

Norepinephrine

Norepinephrine, similar in molecular make-up to epinephrine, is also responsible for stimulating respiration and increase blood pressure and heart rate. Norepinephrine also controls attentiveness, learning, and mood (Limpy, 1999).

Meth, like serotonin and epinephrine, blocks the reuptake of norepinephrine into the pre-synaptic neuron, causing the effects of norepinephrine to be heightened (ibid). For example, during a meth high, users experience increased breathing, heart rate, and blood pressure. However, once the user begins to crash the individual has a greater difficulty learning, as the ability to ‘pay attention’ has been impaired. Furthermore, the user experiences drastic mood swings.
(Meth Project, 2012).

Damaged Neuron Versus Normal Neuron

Neuron Damage

As mentioned earlier, meth inhibits the efficient functioning of dopamine, serotonin, norepinephrine, and epinephrine pathways however, methamphetamine also damages the neuron itself, further negatively impacting the nervous system (Limpy, 1999). Neuron death not only affects the release of these specific neurotransmitters, but other neurotransmitters as well, making it difficult for the nervous system to send and receive signals. This can cause the user to experience difficulty in learning, memory, paying attention, controlled movement, regular emotions, and making rational decisions (Meth Project, 2012). Once damaged, the neurons cannot be fully replaced, altering the biochemistry of the brain and nervous system all together (Meth Project, 2012).

Areas of The Brain Affected by Meth

The image to the left depicts the sections of each brain that meth impacts. In short, meth begins damaging the neurons of the nervous system even at first use. It is for this reason that methamphetamine is considered one of the most dangerous illicit drugs.


Meth and Brain Damage

Long-term meth addiction use can cause extensive damage not only to the body, but also to the brain. Some damage may be irreversible. Continued methamphetamine abuse can severely damage dopamine and serotonin neurons, affecting how a person feels, acts and thinks. Severe damage to these neurons could cause a user to experience symptoms of depression, paranoia and hallucinations.

Meth abuse can also affect the blood pressure. Long-term abuse can cause damage to blood vessels in the brain, causing brain bleeds and an increased risk of stroke. Toxins from the drug can impair memory, cause a loss of motor skills and coordination, and severely influence a decline in intelligence.


Conclusion

Just like other drugs, methamphetamine use can harm our body in many ways. Heart damage caused by methamphetamine may be irreversible in some people. But for many, it’s entirely possible to improve heart health or even reverse the damage. The fundamental part of reversing heart problems caused by meth is to stop taking the drug.

Methamphetamine treatment centers nowadays allow men and women to get much-needed help and assistance that can ultimately lead to a healthier heart and happier life.