imagine a drug so powerful that it has the capacity to profoundly modify the structure and function of your neural networks subvert the brain's reward mechanisms and induce extensive neurological disruption this scenario is not a fictional narrative in fact it is the genuine effect of methamphetamine on the brain a single dose of methamphetamine is sufficient for it to initiate a Cascade that has long-term con sequences on the brain these alterations can range from minor to significant and they differ from Individual to individual in this video we will methodically examine the effect of methamphetamine on the brain from a neurop biological perspective so let's get started and let me take you through these mechanisms first neurotransmitter disregulation a Cascade of disruption we know that methamphetamine significantly increases extra cellular dopamine and it does this by not only blocking the dopamine transporter but also interferes with vmat the vesicles that package dopamine in the preoptic neuron I've covered this in more detail in the video where I cover the differences between amphetamine versus methamphetamine so check that one out due to methamphetamine structural similarity to other monoamines such as serotonin nadrin and dopamine can actually enter these neurons dopaminergic neurons serotonin neurons and noradrenergic neurons either through active transport or passive diffusion and when it does that it can result in the release of dopamine noradrenaline and to a lesser extent but still significant serotonin additionally methamphetamine also inhibits the enzyme monoamine oxidase Mao and by doing this it prevents the breakdown of dopamine noradrenaline and serotonin therefore further increasing levels of these neurotransmitters in the extracellular space when you consider the impact on methamphetamine and the amount of neurotransmitters released this is significantly more th an any of the other agents that we know for example cocaine or amphetamine why is this significant because too much of these neurotransmitters is not healthy methamphetamine therefore induces a hyper dopaminergic State and also a hyper noradrenergic state furthermore the serotonergic balance is affected and overall this disrupts mood behavior and cognition but at the molecular level this monoaminergic storm if you want to think about it that way results in synaptic plasticity changes receptor do wn regulation and also altered neuronal excitability so the result of this hypodopaminergic storm is a short-lived Euphoria within there is the consequence of neurotransmitter depletion that leads to a significant crash two a sympathomimetic storm affecting the cardiovascular system and the cerebrovascular system the excess nor adrenic activity results in cardiovascular strain hypertensive crisis and also techi arhythmia both of these aspects can impede the blood flow to the brain chronic exposu re to methamphetamine can result in structural and functional cardiac changes including cardiomyopathy and that can further affect the blood flow and the per usion to the brain and other parts of the body the significant nor adrenic activity activates alpha 1 receptors now these are adrenic receptors that are also present in the prefrontal cortex and these receptors are activated excessively they're associated with two key aspects one endothelial Vaso constriction therefore cerebral profusion re duces decreased blood flow to the brain and two excessive activation of alpha 1 receptors in the prefrontal cortex moves the individual from from cognitive flexibility towards what we call cognitive constipation cognitive rigidity so this is the same principle that happens in ADHD when we're treating it where if there's too much stimulant it can result in cognitive rigidity stimulus bound responses and impaired decision-making capabilities so this decreased cerebral profusion is not just theoret ical evidence shows that methamphetamine Alters the blood flow to the brain with acute use increasing blood flow to certain regions but chronic use resulting in hypop perfusion and this can have significant implications for brain metabolism and perfusion and that's why on scans often we may see significant white matter hyperintensities in individuals with chronic exposure to methamphetamine these white matter hyperintensities are often consequences of vascular insults three methamphetamine leads e which is an increased focus on drug rated cues two a diminished ability to experience pleasure and reward and a heightened stress response when not using the drug and this is due to a decrease in the reward experience and three imped decision-making capabilities particularly compromised executive function which is necessary for appropriate judgment you see this stage process that leads the person towards addiction is known as the vental to Dorsal shift and what that means is what begins initia -making process actually bypasses the prefrontal cortex and goes straight to the Primitive area so the individual is completely driven by primitive impulses towards seeking the drug and these are the three steps of liking initially and then addiction is moving towards wanting and finally seeking and neuroimaging has shown that as addiction progresses what happens is it is the cues associated with the drug use that that begin to trigger intense drug cravings and drug seeking behaviors through the mine release rather than the actual drug so let's simplify this concept and see what's happening to the individual so now imagine someone who's addicted to methampetamine so when something happens that reminds them of the drug let's say a friend is called or they're going to hang out at a place where they normally use it or just even seeing a place that's associated with the substance use or the methamphetamine use their brain lights up the nucleus cumbent lights up this is like pressing a butto ad you might use techniques such as distraction maybe going out for a morning walk exercise and using social contacts for reward but for someone with addiction the brain's want button get stuck on I want the drug because of a process known as long-term po iation it's like the drug cue the drug reminder is so strong that it drowns out all other competing stimuli or thoughts and it makes it much harder for them to resist the attraction to the drug furthermore because of the decrease reward that th vidual's physical activity increases when they take the drug so they become more hyperactive or they have exaggerated emotional responses after taking taking the same amount or even a lower amount of the drug the issue with this is that it's a sign of lasting changes a sort of memory that can make someone more likely to relapse or more likely to start the drug again even after they've stopped for an extended period of time because it's almost like triggering off the whole Cascade with a single u sitization is due to dopamine release in the nucleus cumbent and glutamatergic activation in these same areas so these two neurotransmitters amplify the addiction potential and this contributes greatly to the risk of relapse and the ongoing addiction cycle five neurotoxicity and neurod degeneration here there is a process of oxidative stress mitochondrial degeneration all the way towards cell death known as apoptosis we know that excessive release of neurotransmitters contributes to oxidative st ne cells but they also regulate the environment of the brain so not only are the immune cells responsible to reduce neuroinflammation if they are excessively activated due to a range of reasons they can set up a neuroinflammatory Cascade that affects neurotransmitters affects the endothelium which is perfusion and this again isn't just theoretical neuroimaging Studies have demonstrated that methamphetamine users over the long-term tend to have reduced neuronal density and integrity especially in so connected to the frontal cortex so I've covered this in more detail in the video and understand the brain so do check that one out now what postmortem analyses have shown is that methamphetamine users exhibit pronounce reductions in strial dopamine transporter so the dopamine transporter is necessary for the uptake of dopamine but methamphetamine users have also shown reductions in tyrosine hydroxylase the enzyme necessary for the production of dopamine and a range of other dopaminergic marke ecutive function cognition and motti function when we further look at neuros pychological testing here we see abnormalities in executive functions such as working memory attention judgment problem solving all of which are really really important for daily functioning there is also evidence of neurocognitive Aging an accelerated decline of cognitive dysfunction so emerging evidence suggests that methamphetamine May accelerate the neurocognitive aging process leading to premature cognitive decline amine used has shown great matter volume atrophy but also changes white matter Integrity white matter tracks facilitate neuronal transmission and I mentioned that olgod dendrites form an important part of these white matter tracts so for example white matter tracts are significantly affected in conditions like multiple sclerosis so that gives you an idea about how neurological symptoms from multiple sclerosis are linked to white matter tract dysfunction you can imagine if white matter tracts are vity alterations so neuroimaging Studies have also shown that the various networks that need to be functioning appropriately are disfunctional and as I mentioned white matters help in that connection so therefore functions such as cognition activity emotion behavioral activation fight andlight responses these all depend on a range of networks such as the salience network the default mode Network the executive control Network and we know that these can be significantly affected in methamphetamine miological studies are suggesting a link between chronic methamphetamine use and an increased risk of developing Parkinson's disease implicating methamphetamine as a risk factor for the development of early signs or symptoms of parkinsonism and whil this is a link there is a biological plausibility because we know that methamphetamine use can result in a hypodopaminergic state what I mean by that is a reduced dopaminergic State through destruction of neurons in the basil gangle and the substanti sychosis now in some individuals due to a range of vulnerabilities genetic factors this methamphetamine Associated psychosis can result in a schizophreniform psychosis or even the illness such as schizophrenia and the mechanism is due to a hypodopaminergic state in the mesolimbic areas that mediate schizophrenia based on the dopic hypothesis of schizophrenia but it doesn't just stop there there are other Neuropsychiatric implications so other neuros psychiatric disorders due to the range of neur ch peripheral immune mediators or inflammatory mediators can pass but overall there is a reasonable Shield that protects the brain from the external Invaders if you want to think about it that way but with methamp fet use what happens is that this brain protection is compromised and that happens because of oxidative stress due to neuroinflammation the Cascade that I mentioned earlier reduce perfusion of the brain and when the bloodb brain barrier is compromised this can then set up a further Cas em but you see when they start attacking these antigens there is the aftermath there is the consequence of neuroinflammation that affects the brain as well so that then brings up us to the immune neuro into play here what happens is methamphetamines effects on activating neuroinflammation results in excessive cyto kind release so cyto kindes there are anti-inflammatory ones there are inflammatory ones but essentially what happens is when neuroinflammation occurs oxidative stress mitochondrial de o due to the immunological modulatory aspects being affected now you've got a triple whammy oh baby a triple or you've got a further exacerbation of the entire process making the overall brain really compromised and the thing here is that we know that neuroinflammation is associated with neurod degeneration so can result in a range of neurodegenerative conditions moving forward in time number nine endocrine disruption here there is a significant impact of methamphetamine on the HPA axis the hypo for optimal cognitive function so this contributes to the overall dysfunction of the brain and finally number 10 the gastrointestinal tract and the autonomic nervous system dysfunction we know that the gut brain axis one of the key mediators is the vagus nerve the vagus nerve also is linked to the autonomic nervous system so this is where we have a disruption of the gut brain axis and also autonomic nervous system dysfunction that overall disrupts the homeostasis impacting on symptoms affecting ect the brain so to summarize methampetamine is not just a simple stimulant it's a really powerful agent that can cause chaos for the brain resulting in a spectrum of changes and we saw it results in a spectrum from molecular changes to behavioral consequences to neuroinflammation to neurod degeneration with many of these effects lasting long after the drug has left the system and what compounds this is the addiction the Cascade of addiction that may maintains use many of you in the previous vid eally appreciate your support I look forward to seeing you in another video soon until then stay curious bye-bye"

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• Methamphetamine profoundly modifies neural networks and subverts brain's reward mechanisms, inducing extensive neurological disruption even with a single dose.
• Methamphetamine significantly increases extracellular dopamine by blocking dopamine transporter and interfering with vesicles, leading to hyperdopaminergic and hypernoradrenergic states, impacting mood, behavior, and cognition.
• Chronic methamphetamine exposure results in cardiovascular strain, hypertensive crisis, and techiarhythmia, affecting blood flow to the brain and causing structural and functional cardiac changes.
• Methamphetamine addiction involves a ventral to dorsal shift in decision-making processes, impairing executive function and leading to intense drug cravings triggered by drug-related cues.
• Long-term methamphetamine use leads to neurotoxicity, oxidative stress, mitochondrial degeneration, neuroinflammation, neurodegeneration, endocrine disruption, gastrointestinal tract dysfunction, and autonomic nervous system dysfunction, causing lasting changes in brain structure and function.