Transcription
Hi everyone, welcome to Psychiatry Simplified. I'm Dr. Seil Regga, consultant psychiatrist.
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 consequences 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 neurobiological 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 extracellular dopamine, and it does this by not only blocking the dopamine transporter but also interferes with VMAT, the vesicles that package dopamine in the presynaptic 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's structural similarity to other monoamines such as serotonin, noradrenaline, and dopamine, it 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 of methamphetamine and the amount of neurotransmitters released, this is significantly more than 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 hyperdopaminergic state and also a hypernoradrenergic 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 downregulation, 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 noradrenergic activity results in cardiovascular strain, hypertensive crisis, and also tachyarrhythmia. Both of these aspects can impede the blood flow to the brain. Chronic exposure to methamphetamine can result in structural and functional cardiac changes, including cardiomyopathy, and that can further affect the blood flow and the perfusion to the brain and other parts of the body.
The significant noradrenergic activity activates alpha-1 receptors. Now, these are adrenergic receptors that are also present in the prefrontal cortex, and these receptors are activated excessively. They're associated with two key aspects: one, endothelial vasoconstriction, therefore cerebral perfusion reduces, decreased blood flow to the brain; and two, excessive activation of alpha-1 receptors in the prefrontal cortex moves the individual 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 perfusion is not just theoretical. 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 hypoperfusion. 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 to a cascade of addiction by excessively stimulating the mesolimbic pathway, and it does this by flooding it with dopamine. Whilst in the acute stages there is a flood of dopamine, chronic use of methamphetamine reduces dopamine levels in the key reward pathway, the mesolimbic pathway, and this has been confirmed by studies showing lower dopamine levels in methamphetamine users' brains.
Now, with chronic use, what happens is a series of neuroadaptations that go through three key steps: first, incentive salience, which is an increased focus on drug-related 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, impaired 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 ventral to dorsal shift. And what that means is what begins initially as a goal-directed action, after the process of sensitization, after these neuroadaptations take place, the individual moves from goal-directed action towards habitual action. So, essentially, the individual is driven by cues and impulses rather than actually the prefrontal cortex making a decision and then the individual going towards goal-directed action. This ventral to dorsal shift, the dorsal aspects is essentially the striatum and the primitive parts of the brain. So, what happens is the decision-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 begin to trigger intense drug cravings and drug-seeking behaviors through the release of dopamine in the nucleus accumbens, as opposed to the actual drug releasing dopamine. So, individuals don't get the dopamine from the drug anymore. Instead, it's the cues in the environment that results in the dopamine release, and that's what results in the seeking behavior with these cues. But when they actually finally use the substance, they have minimal dopamine release in the nucleus accumbens.
So, think about that for a bit. It's the cues, smells, a phone call, paraphernalia, that trigger the dopamine 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 methamphetamine. 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 accumbens lights up. This is like pressing a button, a lever in the brain that says, "I want methamphetamine now."
If you're not addicted, and you get the same reminder, we have other competing stimuli, other competing thoughts that will pop into your head, including the prefrontal cortex making an appropriate judgment, and that makes you decide not to go out to seek that particular drug. So, you have the inhibitory impulse control that's present because the prefrontal cortex weighs up the risks and benefits to arrive at an appropriate judgment. So, instead, 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 gets stuck on "I want the drug" because of a process known as long-term potentiation. 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 decreased reward that they experience when finally using the drug, one requires ever-increasing amounts of methamphetamine to attain the same euphoric effects.
Four, behavioral sensitization. What happens when the individual stops using, the relapse that they experience, and the subsequent effect of the drug after reusing it? This process is known as behavioral sensitization. Evidence tells us that continuous exposure to methamphetamine results in a process known as behavioral sensitization. What this means is, over time, the individual's physical activity increases when they take the drug, so they become more hyperactive, or they have exaggerated emotional responses after 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 use.
So, behavioral sensitization is also known as reverse tolerance, where after repeated use of the drug, instead of the tolerance occurring where the response to the drug diminishes, here the opposite happens: the response to the drug actually becomes stronger. Some clues towards behavioral sensitization include, for example, increased blinking, talking really fast, having higher energy levels, feeling more lively, stereotypies, or sort of abnormal motor movements or tics. And the mechanism of behavioral sensitization is due to dopamine release in the nucleus accumbens 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 neurodegeneration. 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 stress. It results in mitochondrial dysfunction and mitochondrial damage. Both of these contribute to the process of neuroinflammation. Once the neuroinflammatory cycle starts, it affects astrocytes, microglia, and results in oligodendrocyte destruction.
What does this all mean? Oligodendrocytes form the myelin sheath; they're important for neuronal transmission. So, you can imagine when these oligodendrocytes are dying, it affects neuronal transmission. At the molecular level, astrocytes and microglia are important immune 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 the dopaminergic areas, and this correlates with cognitive, motor, behavioral deficits that occur in users.
So, let's look here specifically at what are the neurodegenerative aspects that have been identified, and there are quite a few. So, firstly, striatal degeneration. The striatum is the basal ganglia. The ventral striatum is the nucleus accumbens, which was part of the reward pathway, but then you have the caudate, putamen, the substantia nigra. These are important parts responsible for movement, and of course, they're also connected to the frontal cortex. So, I've covered this in more detail in the video "Understand the Brain," so do check that one out.
Now, what postmortem analyses have shown is that methamphetamine users exhibit pronounced reductions in striatal 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 markers as well. And this is indicative of dopaminergic degeneration.
So, when we think about how is the striatal degeneration linked to the clinical picture here, we can see movement disorders that are present. We can see slowing or tremors or symptoms similar to what we might see in Parkinson's disease, and I'll come to that in just a bit. Similarly, PET scans and MRI scans have also shown deficits and abnormalities in dopaminergic and serotonergic markers, such as that VMAT2, similarly impacting executive function, cognition, and motor function.
When we further look at neuropsychological 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. And this is of significant concern because what we sometimes see clinically is an individual's cognition is significantly affected so that they're functioning at the level of someone 20 or 30 years older. And I mentioned that we often see vascular deficits, so sometimes there might be even an overlap with a vascular dementia type picture. So, this is a serious issue that we see in clinical practice.
There's also evidence of structural brain alterations in the gray and white matter. So, chronic methamphetamine use has shown gray matter volume atrophy, but also changes in white matter integrity. White matter tracts facilitate neuronal transmission, and I mentioned that oligodendrocytes 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 affected through methamphetamine use, one can also experience a range of neurological deficits.
So, besides white matter hyperintensities that I talked about, imaging techniques such as diffusion tensor imaging or DTI, that sort of gives us the white matter integrity, shows that white matter tracts are significantly affected or altered in methamphetamine users. So, broadly, not only white matter integrity is affected, but also connectivity. And talking about connectivity, there are also structural connectivity alterations. So, neuroimaging studies have also shown that the various networks that need to be functioning appropriately are dysfunctional. And as I mentioned, white matter helps in that connection. So, therefore, functions such as cognition, activity, emotion, behavioral activation, fight-or-flight 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 users.
I talked earlier about dopamine neuron degeneration. This is one of the concerns because movement disorders, a possible gateway to parkinsonism, is something of concern. So, chronic methamphetamine misuse leads to psychomotor impairment, such as decreased motor speed and coordination. These effects can be due to the direct neurotoxic effects of the drug on key basal ganglia structures and neurons, but also because of the drug's effect on the cortical areas that control these motor functions. Epidemiological 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 whilst 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 basal ganglia and the substantia nigra. And we know that Parkinson's disease is essentially dopamine neuron degeneration in the basal ganglia area, so substantia nigra, and of course, the connections from the substantia nigra to the striatum. And it is something that is of great concern.
Point six, methamphetamine-induced psychosis or MAP, methamphetamine-associated psychosis. Now, I've covered this topic in a lot more detail in another video, so do check this video out. But essentially, methamphetamine is associated with a high risk of psychosis. 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 dopaminergic hypothesis of schizophrenia. But it doesn't just stop there. There are other neuropsychiatric implications. So, other neuropsychiatric disorders, due to the range of neurotransmitter dysfunction, the structural, the functional impact on the brain, disorders such as sleep disorders, anxiety, depression can be part and parcel of methamphetamine use.
Seven, the blood-brain barrier disruption. Now, we know that the blood-brain barrier plays a really important role and acts as a shield in protecting the brain from a lot of peripheral aspects such as immune inflammatory mediators. Now, of course, there are permeable areas where the blood-brain barrier has gaps through which 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 methamphetamine 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, reduced perfusion of the brain. And when the blood-brain barrier is compromised, this can then set up a further cascade of neuroinflammation because what happens is we'll see as part of the immune and inflammatory mediators that there can be a cross-reactivity, which means that antigens that are present because of oxidative stress in the rest of the body, these ones can look like invaders to the brain's immune cells, and they can start producing antibodies that start attacking these antigens. They are the body's antigens, but they look different, and the immune cells, the brain's immune cells, have started attacking them. 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 us to the immune-neuro interplay here. What happens is methamphetamine's effects on activating neuroinflammation results in excessive cytokine release. So, cytokines, there are anti-inflammatory ones, there are inflammatory ones, but essentially, what happens is when neuroinflammation occurs, oxidative stress, mitochondrial degeneration, the balance tips towards much greater inflammation. Now, these inflammatory cytokines, they affect the amygdala, so you get heightened responses, very similar to what happens with the substance as well. But you also get a decrease of dopamine and other neurotransmitters in the areas where they're needed, such as the prefrontal cortex and the striatum. So, essentially, what it does is not only through the direct drug effects, the other indirect drug effects that I just talked about earlier, but also due to the immunological modulatory aspects being affected. Now, you've got a triple whammy. Oh, baby, a triple whammy. 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 neurodegeneration, so it 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 hypothalamic-pituitary-adrenal axis. You see, whenever there is a stressful response, the amygdala, the corticotropin-releasing factor, adrenal glands, and the release of cortisol, all of these play a part to reduce stress, but to also reduce inflammation at the same time. We saw earlier that the addiction cycle results in heightened stress, therefore results in hormonal perturbations, hormonal dysfunction. And we know that a range of neurotransmitters rely on these hormones – testosterone, estrogen, progesterone – 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 the GI, the change in the gut microbiome, but also thermoregulatory changes linked to autonomic nervous system dysfunction, blood pressure changes that affect perfusion across the body, particularly the brain as well. So, these effects really underscore methamphetamine's capacity to disrupt overall body homeostasis, which is really the balance that we all need, and cause multi-systemic adverse effects. And we know that the brain and the body are connected. Therefore, what happens in the body will also affect the brain.
So, to summarize, methamphetamine 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 neurodegeneration, 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 maintain use.
Many of you in the previous videos have highlighted the comments and highlighted the devastating effects of methamphetamine on friends and family members. I hope that this video has given you an overview of methamphetamine as a drug and the neuroscientific explanations for the impact on the brain.
Thank you very much for joining me today. If you like this video, please don't forget to leave us a like, leave us comments, and let us, of course, know what other videos you'd like. Thank you so, so much for supporting this channel. I really appreciate your support. I look forward to seeing you in another video soon. Until then, stay curious. Bye-bye.