In 2021, according to the National Institute on Drug Abuse, over thirty thousand people overdosed due to the use of methamphetamine in the United States. According to the National Survey on Drug Use and Health from 2019, 4% of people in the United States struggle with a methamphetamine addiction. A study from 2009 showed that the odds of committing a homicide were nearly nine times greater for methamphetamine users. We see this reflected within North America with crime rates closely correlating with the rates of Meth use in most communities. The long-term effects of meth include physical ailments like kidney damage, cardiovascular damage, and other issues, but physiologically meth allows for an entire rewiring of your brain. Family and friends of individuals who have meth addictions often describe the changes they see within their loved ones as swift and drastic, with a kind and loving individual being turned violent and aggressive. The individuals are seen to have entire personality changes, which are often represented in their future mental struggles with depression and anxiety being the prominent examples. Furthermore, meth is a substance that only a few are able to recover from with relapses being frequent and in many cases inescapable. This data begs the question what effect does meth have on the human brain, and to what extent can the neurological damage be reversed?  

In our study we wish to answer these questions and examine the neurological reasoning for why these drugs are so hard to quit. 

Our project is a research project, which means we didn't have an experimental method in mind. However, in our research, we organized our broad questions into sections with main areas focusing on the repercussions on society, the individual, and then further generations. We looked into what certain neurological systems look like in a healthy brain and an addicted brain. This started by first looking into research studies as a going-off point and then explaining why these things happened. 

Introduction: 

The man-made drug commonly known as Meth is a central nervous system stimulant. It operates similarly to other stimulants but allows for the massive release of neurotransmitters such as dopamine, or norepinephrine. In a healthy brain, dopamine is released as a mechanism for reward, such as eating, moving, or socializing. With repeated meth use the brain’s system for reward becomes less sensitive to dopamine. This requires the brain to require more stimulants to release an amount of dopamine that can be properly felt. Over time, this reduces the amount of dopamine receptors available as well as the brain's ability to produce dopamine. Additionally, we also see a decrease in the amount of neurons in the central nervous system.  These cells cannot be replaced, and if lost are often lost forever. 

What are the immediate effects? 

The immediate effects of recreationally using methamphetamine are closely linked to the dopamine release that follows. Meth acts as an extreme stimulant that causes dopamine to rapidly exit the synapse(space) between neurons and inhibits the neurotransmitter's ability to be reabsorbed. This overstimulates the sympathetic nervous system, triggering what is known as the “flight or fight” response. This leads to the dilation of the eyes, increased blood to the muscular system, and an increased heart rate. The rapid increase of pressure on the blood vessels allows for higher chances of strokes and blood clots. This in the moment becomes a euphoric experience for the user. However,  in the future, it severely damages the ability of the neurons and neurotransmitters to be able to properly produce and transport dopamine and serotonin across the synapse. This becomes an issue of neurotoxicity since dopamine is released in such massive amounts and then unable to be reabsorbed into the presynaptic neuron. This allows for the dopamine to remain in the synapse for longer, intensifying the signal. Over time, as the neurons are constantly overstimulated, the nervous system begins to regulate the amount of dopamine receptors available. The dopamine receptors decrease in quantity over time. This makes it more difficult to return to average life after drug use. The user is unable to feel an adequate amount of dopamine when doing healthy tasks. For instance walking, eating, or resting. This only increases methamphetamine dependency in the long run, making it even harder to quit.

What are the implications for society? 

This brings in the question “Why is this important?” meth use is a human issue that is greatly reflected in crime rates, safety, and quality of life. The use of meth leaches into different aspects of life that affect many others in vulnerable positions. The implications of meth are widespread, with children often being exposed to fumes early in life due to rampant drug use in certain communities. The prison system is overwhelmed with the dental needs of prior meth users. The 2021 National Survey on Drug Use and Health reported that in 2020 meth-related visits to the ER ranked 3rd at 11.29% in the United States. Additionally, crimes including identity theft have been closely correlated with meth production and use recently. There are also more complex methods of distribution being popularised to confront increased regulation and police attention towards meth distribution. The 2018 NDTA reports that drones are increasingly being used to distribute meth. In 2020, two Arizona residents were arrested in Yuma for flying 24.9 pounds of meth across the border, using a drone. The correlation between Meth and increasing social and criminal issues is clear. This is an incredibly complex issue when you take into account the varying approaches society has taken to limit the spread of drug use. The issue with Meth specifically that differentiates from other drugs such as alcohol, and cannabis. Meth has a very special composition that allows for an almost immediate addiction to take place. This is in contrast to other addictive substances that develop more addictive natures over time, such as alcohol, which primarily relies on persistent human engagement to become addictive. Methamphetamine is a substance that both neurologically alters the user and detrimentally harms society, reform is necessary to confront these grave issues concerning safety and drug abuse. 

Chemical structure of Meth: 

C10H15N, better known as Methamphetamine, is a member of the class of amino acids known as amphetamine and carries a methyl substituent. Its role as a neurotoxin and a psychotropic drug is a large part of its chemical identity. Its IUPAC name is (S)-N-methyl-1-phenylpropan-2-amine which reflects its chemical composition (PubChem). To understand the role and actions of meth it is important to include its two functional groups. Meth consists of an Aromatic ring and an Amine group. The Aromatic ring (C6H5) which is also a benzene ring, plays a crucial role in its ability to interact with dopamine receptors. The Amine group -NH2 is also crucial for meths ability to cross the blood-brain barrier. Together, this combination increases its lipophilicity (ability to dissolve in fats and lipids), allowing it to penetrate cell membranes. Additionally, this structure is extremely similar to the neurotransmitter known as dopamine with both sharing the same phenol group, which allows for meth to easily mimic dopamine and bind to dopamine receptors. Methamphetamine works mainly by increasing the release and blocking the reuptake of neurotransmitters. This permits dopamine to remain in the synaptic cleft, unable to be reabsorbed in a regular amount of time. Other neurotransmitters such as glutamate (A major excitatory neurotransmitter) and calcium are often associated with neurotoxic effects in the brain as a result of the neurons being overly excited and continuing to fire to the point of detriment. This is one of the effects that methamphetamine can have due to its ability to mimic dopamine and attach to dopamine receptors. These neurotoxic effects can serve to damage the dendrites (receiving portion of the neuron) and further inhibit the healthy and normal release of dopamine within the neuron cells. The unique chemical makeup of meth is one of the driving factors for its addictive nature and neurological implications. 

How does Meth allow for oxidative stress and neuroinflammation?

Oxidative stress caused by meth use can in turn allow for inflammation of the brain to occur. Oxidative stress is essentially an imbalance of free radicals (type of unstable molecules) and antioxidants that can damage brain cells. The free chemical radicals are not properly counteracted by antioxidants. Oxidative stress and elevated dopamine present outside the vesicles of the neuron due to repeated use of methamphetamine may cause microglial cell (immune system cells in the brain) activation. Microglial cell activation causes neurotoxic damage by releasing proinflammatory cytokines (signal molecules that promote inflammation). Meth disrupts the blood-brain barrier by allowing for oxidative stress in endothelial cells(cells lining blood vessels). The destruction of endothelial barriers increases transendothelial leukocyte migration, which is the migration of white blood cells across the blood vessel wall to attend to inflammation, contributing to tissue damage and neuroinflammation. This results in grave long-term effects on the neural system which leads to the deterioration of the reward system of the brain.

What structural changes occur to the brain because of Meth?

1. Striatum - this area of the brain, which is part of the basal ganglia (structures involved with motor control), is crucial in reward processing (mesolimbic pathway), voluntary motor control (substantia nigra), and also the establishment of habits. When meth acts upon this structure the changes are significant. Meth acts by increasing the amount of dopamine released and preventing its reuptake. This action allows for large feelings of euphoria following meth use. Over time, the chronic use of methamphetamine allows for the generation of reactive oxygen within presynaptic neurons. This oxidative stress allows for lipid peroxidation and protein carbonylation, which results in neural death. Neuroimaging has enabled us to see a decrease in dopamine transporters in the striatum with meth use. This reduces the ability of dopamine to be reuptaken into the synapse. Meth use has also been seen to reduce grey matter in the striatum indicating neural atrophy because of neurotoxicity. 
2. The prefrontal cortex- The prefrontal cortex is involved with the actions of higher thought, voluntary movement, and decision-making. All are crucial for the human mind. Methamphetamine affects the mesocortical pathway, a dopamine pathway from the ventral tegmental area and the frontal cortex. Additionally, this structure has also been seen to have irregularities in individuals with schizophrenia. Meth use allows for a higher release of dopamine leading to receptor desensitization. This blocks and greatly inhibits normal dopamine signals and the reward system of the brain. Meth allows for the larger release of glutamate the most abundant amino acid in the brain and an excitatory neurotransmitter. This allows for the gated calcium channels to open. This creates an influx of calcium, activating calpains which have a crucial role in cytoskeletal remodeling. This can cause damage to the cytoskeletal proteins of the brain, and therefore damage to the prefrontal cortex’s neurons. MRI studies have also concluded that meth use can result in both cortical thickness and white matter declining. This damages goal-directed behavior and higher thinking.
3.  Hippocampus- The hippocampus is crucial to memory formation and spatial conceptualization. Meth allows for excessive serotonin and dopamine leading to glutamate release. This in turn causes a calcium overload and allows for the mitochondria to become dysfunctional in many cells. This causes cell self-destruction, and it initiates its demise, often known as neuronal apoptosis. This impairs memory retention and the ability to absorb information. Meth also serves to suppress the neurogenesis (creation of new neurons) process in the hippocampus. Methamphetamine does this by harming growth factors and preventing the development of new neurons. This further contributes to the decrease in proper learning retention and memory storage. Structurally meth enables atrophy in the hippocampus due to chronic meth use. This severely damages the ability to remember past moments in one's life and create new memories. 
4. Amygdala- The amygdala has an important role in managing emotions associated with anger, fear, and survival. Methamphetamine overactivation of the amygdala caused by excessive dopamine increases emotional reactivity. This is shown in the heightened aggression and anxiety that meth users often experience. Excessive dopamine and glutamate can also lead to changes in the synaptic structure of neurons. This decreases receptor density in the amygdala, which affects memory formation. This in turn can lead to emotional dysregulation. Structurally the amygdala has been shown to experience hyperactivity above usual in stressful situations in meth users, increased area, and also new connectivity to the prefrontal cortex. This explains the unregulated emotions found in meth users, as well as the predisposition for violent outbursts.
5. Cerebellum - The cerebellum is crucial in maintaining balance and motor control. Chronic meth use allows for the constant release of oxygen species and reactive nitrogen in the brain. These substances contribute to oxidative stress, which damages cellular structures within the cerebellum. Additionally, meth allows for the destruction of dopaminergic neurons in the cerebellum. Methamphetamine also allows for the reduction of grey matter within the cerebellum. Purkinje cells, which regulate and coordinate motor movements, are also affected. The impairment of dopaminergic neurons can contribute to irregular stimulation of Purkinje cells. This is seen with chronic meth users lack of coordination and control over their movement in many cases. 

 

What are the impacts on grey matter and neuronal integrity?

Meth produces long-term consequences on the neural systems present in the human brain.  The impacts of meth-induced dopamine reuptake and overstimulation can result in auto-oxidation which leads to further oxidative stress and neural degeneration. Meth also can induce apoptosis, self-induced cell death, leading to a reduction in neuron density. Meth can activate the mitochondrial pathway allowing for mitochondrial dysfunction over time due to oxidative stress. This can induce a decrease in ATP production, permitting cytochrome c, a pro-apoptotic protein, to enable cell death. The increased glutamate(excitatory neurotransmitter) secretion triggered by meth use also serves to overstimulate glutamate receptors. This in turn opens calcium channels, which let in an influx of calcium ions. This influx activates calcium enzymes which degrade cell membranes. Additionally, the excess calcium serves to degrade the mitochondria's depolarization process during the travel of the stimulus down neurons. We see the neural integrity broken down further with the release of microglia cells (neural immune cells). The microglial cells are triggered to release because of methamphetamine. This release allows for a positive feedback loop to occur, which increases the amount of microglia present. Microglia enable the release of pro-inflammatory molecules, like cytokines and chemokines. This serves to exacerbate neural inflammation and oxidative damage to the neural structure. Furthermore, meth can also contribute to the reduction in grey and white matter. This is incredibly problematic because grey matter contains important volumes of cell bodies, and white matter contains vital amounts of myelinated axons. Reductions in these regions could result in a massive decline in cognitive function and motor control. To conclude meth has massive implications on neural integrity which include reductions in dendrite branches and synaptic plasticity. This in the long run can cause irreversible damage to neural communication and connectivity impairing even basic neural functions. 

How do these changes correlate with changes in activity and personality?

Methamphetamine correlates to intense changes in brain function which impact the personality of the user as well. Methamphetamine's ability to induce a large release of dopamine relates to changes in personality and behavior periodically. Over-stimulation of dopamine receptors in the brain creates momentary feelings of pleasure and euphoria that are often short-lived. Over time meth use depletes dopamine receptor concentration, reducing the effectiveness of dopamine and other neurotransmitters. This allows for reduced motivation and activity levels. Meth users may also experience loss of motor control due to this depletion of dopamine. Methamphetamine chemically and structurally alters other aspects of the brain, including most notably the prefrontal cortex. The depletion of dopamine receptors and grey matter in the prefrontal cortex is responsible for emotional dysregulation seen in meth users. Meth's neurotic effect on the user can enable hallucinations and fits of rage. This is mainly due to dopamine activation, and how it damages the mesolimbic pathway the neural passage connecting to the amygdala. Additionally, the chronic and often irreversible damage to parts of the brain can allow for dysregulation of emotional control. The overall reduction in brain volume and structural damage can also exacerbate symptoms of memory loss and personality changes. The memory loss symptom specifically impacts the personality changes by enabling the user to become withdrawn and unable to retain important information. The significant impairments in memory and depletion of the prefrontal cortex enable massive behavioral shifts. This can mainly be attributed to how the reduction in the prefrontal cortex limits critical thinking skills and enables erratic behavior. To conclude, methamphetamine can cause massive changes in the personality and behavior of users due to the meth's implications on instrumental regions in the brain regulating emotional management.

Neurotoxicity and implications?

Methamphetamine can enable the excessive release of dopamine resulting in an extended period where dopamine is present in the synaptic cleft. The increased levels of dopamine in the synaptic cleft and the excessive stimulation of dopamine receptors can lead to the creation of reactive oxygen species. This enables further oxidative damage which serves to negatively impact the brain. The excessive glutamate neurotransmitters that are released due to methamphetamine enable further neuro-damage. This allows for calcium to flow into the neuron. The calcium activates the enzymes such as calpains and phospholipases. These enzymes break down cellular structures, which contributes to mitochondrial dysfunction. Meth also activates microglia, which are the immune cells of the central nervous system, which are normally involved in immune response. When activated, microglia release pro-inflammatory cytokines (chemical messengers) which contribute to neuroinflammation. This inflammation can lead to brain disfiguration and damage in the future.

How does meth affect communications between regions in the brain? 

Methamphetamine can have destructive changes in the brain which limit total brain function and the way different areas of the brain communicate. The dysregulation of the dopamine pathway enables the dysfunction of dopamine-based neural pathways in the brain. The nucleus accumbens a structure in the dopamine pathway and also experiences immense over-stimulation. This causes reward-seeking behavior often known as addiction.  Furthermore, meth also alters signaling between the striatum and the prefrontal cortex which is incredibly harmful. Critical thinking and reward-induced behaviors are often altered in those who have long-standing meth addictions. In the prefrontal cortex, the reduction in grey matter can inhibit the proper regulation of emotions and higher thought. The prefrontal cortex cannot regulate other subcortical regions like the amygdala which severely halts behavioral management. The depletion of white matter in the brain due to oxidative stress also serves to limit communication between different regions of the brain. This effect can in turn enable a loss of higher thought and decision-making skills. The impacts of meth on neurotoxicity in turn lead to the depletion of neural connectivity and communication. The frontostriatal network primarily the PFC, striatum, and thalamus is greatly affected. Leading to gaps in neural flexibility and enabling impaired decision-making. The restructuring of the cerebrum due to meth use can result in immense damage that leads to communication errors between regions of the brain. 

Neuromapping Techniques:

In the modern day there are a variety of new ways to properly scan and map the brain. This includes Functional Magnetic Resonance Imaging which measures the oxidative blood flow in different regions of the brain. This technique works by measuring the changes in the magnetic properties of blood in different parts of the brain. This is helpful because it can show which areas of the brain are active during certain stages of drug use, and also how drug use impairs certain regions of the brain. Diffusion tensor imaging is also very useful in showcasing the functions of the brain. It does this by measuring the diffusion of water along the dendrites of white matter cells. Magnetic Resonance Spectroscopy is also a very common technique. This technology measures the metabolites within the brain and which regions have certain metabolic concentrations. This can be used to monitor neural health by identifying if regions of the brain are using the correct amount of metabolites necessary. This is particularly used for neurodegenerative disorders and is used to see the damage to the neural structures because of methamphetamine. These neural techniques can give a broader view of the impacts meth can have on the brain. 

How does Meth pass through the brain's blood barrier? 

The blood-brain barrier is a selectively permeable barrier that ensures pathogens and other destructive proteins do not pass into the brain. Methamphetamine unfortunately due to its chemical makeup can easily pass through the blood-brain barrier. Methamphetamine is highly lipophilic which means it's able to dissolve within fatty acids. Due to this predisposition, meth can easily travel through cells with a lipophilic membrane. The blood-brain barrier is made up of cells of this nature making it easy for meth to pass into the brain. Additionally, due to the chemical similarities between meth and dopamine, meth can easily be transported into neuron cells from dopamine transmitters. Meth’s ability to pass into the brain impacts the dopamine reward system and contributes to the addictive nature of this drug. Meth enables the release of mass amounts of dopamine further contributing to the cycle of addiction. Over time this use can result in dopaminergic neurons being significantly damaged. This in the future can diminish the effectiveness of human motor control and emotional regulation. Furthermore, since meth can easily damage regions that have significant roles in memory loss, cognitive decline is common. Brain shrinkage is also a common feature because of meth crossing the blood-brain barrier. Meth use can in the future lead to atrophy of the brain, especially with the white matter. This area of the brain is mainly responsible for communication so the damage is often seen in the body with poor motor control and lack of mobility. The inflammation caused by extreme usage of meth is able to severely damage the neuroplasticity of the brain which in many cases is irreversible. 

 

1. Can the brain recover fully?
   1. What steps can be taken in response?
   2. What potential is there to restore the brain to its previous level of function?

 

Methamphetamine abuse has been shown to cause significant brain damage, yet research indicates partial improvement with sustained abstinence and targeted intervention. While changes in certain structural and functional realms occur with the progression of time, the extent of improvement does so on the grounds of duration of abuse, duration of abstinence, and treatment.

 

Possible Brain Recovery -  Partial Functional Restoration

 

Cognitive functions like impulse control and attention improve substantially after more than one year of abstinence, with performance comparable to non-users on measures like the Stroop attention task (a neurophysical test that requires selective attention, cognitive adaptability, and inhibitory control). Comparative studies analyzing the difference in the grey matter volume (GMV) of individuals who had abstained from methamphetamine use for the long-term recovered the most GMV in their brains when contrasted against a human control group.  The cerebellum has been found to play a significant role in decision-making with its part in maintaining memory, predictive ability, and overall ability to control oneself. The cerebellum has been linked to emotion and cognitive function as well. It has been proven numerous times that the GMV in the cerebellum is decreased over time by the use of methamphetamine and, previously, it was theorized that this loss was one that could not be overcome. The Crus I is a region that plays an important part in cognitive function and it was shown the GMV in this particular region was negatively correlated with nicotine dependence, a significant discovery that applies to methamphetamine as well. 

 

 (Source: https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2018.00722/full#B38)

 

Zhang et. al discovered in their study where they used voxel-based morphometry to compare GMV in a group of 44 abstinent individuals who had been abstaining from the drug for the past 14-25 months with a healthy control group of 40 individuals that GMV was increased in the left and right cerebellums of the abstinent individuals, theorizing that this indicates recovery of the cerebellum over time. Additionally, studies have found that the period for which the drug is abstained from is positively correlated with left cerebellar volume as well. 

 

Unfortunately, oftentimes visual-processing areas such as the cuneus and calcarine, important parts of the visual cortex, lose a significant amount of brain volume in this area meaning that relapses from drug-related cues are very common. This damage to the occipital lobe is one of the longest lasting effects of methamphetamine addiction and it persists even after long periods of abstinence. 

 

Potential to Prevent Cell Death

 

Koob et.al investigated the effects of methamphetamine on gliogenesis in the medial prefrontal cortex and found that daily administration of the drug led to significant cell death through apoptosis or necrosis in the brain and decreased gliogenesis. Without glial cells, nerve cells are unable to successfully conduct action potentials potentially leading to negative effects on the function of the prefrontal cortex. 

 

Studies contrasted this with the negative effects on the prefrontal cortex due to traumatic brain injury (TBI) and found that much of the disrupted processes were the same, similar enough for pharmaceutical treatments for those that suffered from a TBI could be applied to methamphetamine addicts as well in order to combat the dangers of cell death (calpain/caspase inhibitors). If these neuroprotective inhibitors were to be used in conjunction with rehabilitative measures, it is likely that there would be more success seen when looking at GMV recovery post-addiction. 

 

The most effective treatments as of now to help cope with the symptoms of methamphetamine withdrawal is rehabilitation and reintegration to society as it activates the prefrontal cortex and allows for the GMV to grow. Other successful treatments include: exercise, in order to increase hippocampal volume and enhance/repair the neuroplasticity that was lost through addiction, mindfulness training (i.e. meditation) in order to strengthen any neural circuits or reward pathways that may have been compromised and lifestyle adjustments such as increased sleep to eliminate toxins and heal the brain while also consuming a nutrient-rich diet that will help replenish the vitamin deficiencies that often go hand-in-hand with addiction, repairing the mind as well. 

 

 

2. What are the genetic implications of methamphetamine? 
   1. Can addiction be a hereditary trait? 
   2. How does methamphetamine influence gene expression?

 

Addiction risk involves complex interactions between genetic susceptibility and epigenetic modifications, with parental substance use potentially influencing offspring through both inherited DNA variants and acquired epigenetic changes. While no single "addiction gene" exists, research highlights multigenerational transmission mechanisms and prevention opportunities. While there is no single gene that is responsible for an individual's susceptibility to fall into substance abuse, studies have shown that the heritability of substance abuse is quite high (~49–70%). However, substance abuse results from a highly complex interplay between an individual's genetic and environmental influences. It is known that factors such as substance abuse during pregnancy, a parent’s psychopathy and criminal activity, low socioeconomic status, and affiliating oneself with peers who abuse substances all increase your likelihood of substance abuse but the biological mechanisms that dictate as to why this happens are largely unknown. 

 

With that in mind, there are hundreds of genes and epigenetic processes that do increase one’s likelihood to fall into addiction and/or substance abuse. One of these processes is DNA-methylation (DNAm), meant to modulate transcription by adding a methyl group onto DNA base pairs, primarily cytosine-guanine dinucleotides; it is heavily influenced by nutritional, chemical, pre- and postnatal environmental influences and psychosocial factors. DNAm has been linked to a wide variety of diseases, both physical and psychiatric, and it has been found to influence the likelihood of an individual to fall into addiction as well. While DNAm does not directly change the genetic code, instead it adds on methyl “tags” changing the way the genes work and whether they’re expressed or not. An increased amount of methylation means an increased possibility that genes which dictate stress response, impulse control, and are responsible for protecting yourself are turned off, making an individual more likely to abuse substances. This is something that can be passed down to the offspring of anyone who is under the influence of addiction, where DNAm is altering the pleasure and memory regions of the brain making addiction even more long-lasting and hard to overcome. 

 

Meth reduces Pex5 methylation by approximately 14.8x in the prefrontal cortex, which impairs peroxisomal antioxidant defenses (protective systems that help reduce damage from harmful molecules like free radicals)  and promotes oxidative DNA damage (by causing too many free radicals).  Additionally, hypermethylation of Oprm1 (μ-opioid receptor) in the nucleus accumbens blunts natural reward responses which then increases drug-seeking behavior.

 

Drug abuse can cause modifications to sperm that alter the methylation that is occuring in the gametes before they even fertilize an egg, as well as affect histone (type of protein in chromosomes) marks, effectively transmitting a more addiction-prone phenotype to their offspring. Maternal and paternal drug use differently modifies DNA methylation in genes related to our reward system such as BDNF and DAT47. All of these changes correlate with altered gene expression in areas of the brain like the nucleus accumbens (reward and pleasure) and the prefrontal cortex (impulse control). 

 

Other genes that are proven to help “transmit” addiction across generations are variants in Hnrnph1 (a gene that regulates RNA splicing and processing in reward circuits),  SNP rs14251 near HDAC3 (the A allele increases the risk of becoming dependent on meth by 25%, no regulatory link to HDAC3 in human tissue, despite the proximity), and other genes that are in control of dopamine signaling, stress response/adaptation, and impulse control. DRD2 (D2 receptor) is a gene that alters splicing, reducing the function of dopamine autoreceptors which ultimately leads to more drug seeking. Other genes have effects like lessening the potency of the drug by decreasing the dopamine response to it, whether it is your first time using it or not which leads to a positive feedback loop of more drug use that harms your brain and makes you more addicted which leads to more drug use. The gene COMT (Val158Met) plays a role in impulse control and it causes there to be faster dopamine clearance which means that the dosage number keeps going up and it’s more frequent as well. 

 

Genes that are affected by SNP rs14251

 

A high polygenic risk score (PRS), is essentially a summation of the small changes each gene is making in your body and compares it to a different genetic group. If your polygenic risk score is high, you are predicted to start using substances about 2.1 years earlier than the population with a lower PRS. It also means that they have a 34% faster progression into addiction, causing them to become highly dependent more quickly. 

Synapse steps: 

In a normal healthy brain: 

1. Action potential arrival- An electrical impulse travels from the axon (transmits electrical signal) down along the myelinated sheath in the presynaptic neuron until it eventually reaches the axon terminal. 
2.  The arrival of the action potential(electrical impulse) causes voltage-gated calcium channels in the pre-synaptic neuron to open, this allows for calcium to rush into the cell. 
3. The increase in Ca+ in the synaptic vesicles causes the synaptic vesicles to fuse with the pre-synaptic membrane and release the neurotransmitters into the synaptic cleft (the space between neurons) 
4. Neurotransmitters diffuse across the synapse and bind to receptors on the post-synaptic neuron to transmit the neuron signals across neurons. 
5. Binding to the neuroreceptors can either inhibit or enable a response. This action either depolarizes (causes more transmission to other neurons)or hyperpolarizes(stops the transmission) the post-synaptic neuron. 
6. The signal after delivering its message is terminated from the synapse. It is terminated through reuptake into the neuron or is broken down by enzymes in the synapse. 

 

On Meth: 

1. Meth increases the amount of dopamine released from the pre-synaptic neuron. Meth causes an amplification of dopamine release and response. This allows for a larger amount of dopamine to be in the synaptic cleft, which overstimulates the post-synaptic receptors. 
2. Meth then inhibits the intake of dopamine back into the pre-synaptic neuron, Normally dopamine is taken back into the neuron, however, methamphetamine blocks the dopamine transmitter from being reabsorbed. This allows for dopamine to remain in the synapse for longer and enables the continuous stimulation of post-synaptic receptors. This leads to large feelings of ecstasy and euphoria. 
3. Meth can also allow for the dopamine transmitter (actively transports dopamine) to work in reverse, forcing dopamine to be released into the synapse, even when the neuron isn’t actively firing. This allows for abnormal dopamine release that is even more destructive for the brain. 
4. Over time, this excessive use of methamphetamine can lead to damage to the neuroreceptors and allows for neurotoxicity. 
5. This also affects the tolerance of dopamine receptors. When excessive dopamine is released, their tolerance to dopamine increases, which now requires the receptors to be exposed to more dopamine in order to achieve the same effect as before. 

Studies that we used: 

 

Franklin (2002). "Increased Brain Glucose Metabolism After Methamphetamine Abuse in Humans."

This study looked into the amount of glucose released by the brain on methamphetamine in contrast to the control group. This study used positron emission tomography to measure the amount of glucose released in the striatum and the prefrontal cortex. This study found that individuals who used methamphetamine had increased levels of glucose in their prefrontal cortex. This study led researchers to make the connection between changing metabolic rates in the brain and the reconfiguration of neural pathways. 

 

(2004). "Cerebral Cortical Gray Matter Shrinkage in Human Methamphetamine Users." from the American Journal of Psychiatry. 

This study looked into the brain reconfiguration due to Meth use. Using MRI scans researchers concluded that meth use was connected to the depletion of grey matter in the hippocampus and parts of the prefrontal cortex. 

 

Jernigan, T.L., et al. (2005). "Cerebral Morphology in Chronic Methamphetamine Users: A Longitudinal Study." from Neuropsychopharmacology. 

This study investigated brain atrophy in different regions of the brain due to meth use. The study indicated that there was significant evidence to conclude a link between meth use and depletion of grey matter in the brain. 

 

Chou, C.P., et al. (2013). "Functional and Structural Brain Abnormalities in Chronic Methamphetamine Users: A Longitudinal Study." from Journal of Neuroscience 

This study looked into how meth affects the connectivity of brain regions. The study found that over time people chronically using meth could lead to altered connectivity in primarily the prefrontal cortex. This resulted in altered behavior and emotional regulation. This study indicated that meth can reconfigure brain structures. 

 

In a research project, there will always be chances of bias and sample issues within different experimental studies. We tried our best to properly use the information from a variety of reliable sources. 

There could be issues of selection bias for the participants in the studies we mentioned. Addiction center studies may be more geared towards overstating the dangers of drugs and painting them in a particular light.  Additionally, studies or sources sometimes may overgeneralize the symptoms and impacts of drug use. Meth is a substance that does not result in the same effects for all people. Furthermore, meth is also a more recent phenomenon, and because of this, it is often hard to get full certainty on the long-term effects. Meth also has a social stigma attached to it. This results in skewed data in some cases because a certain outcome is desired. 

Overall we tried to draw from a variety of sources that had notoriety. Through this, we were able to compile information that was accurate for our project.  

 

 

 

Methamphetamine has profound effects on the function of our brain, altering it drastically, primarily by hijacking the dopamine system. It forces neurons to release an excessive amount of dopamine which then blocks the reuptake of dopamine, leading to temporary euphoria and long-term damage to dopaminergic pathways. With chronic use, dopamine stores deplete, diminishing the effects of natural reinforcement and increasing addictive behavior as the postsynaptic receptors are desensitized. On a structural level, meth causes widespread damage to the brain, particularly in gray matter-heavy regions like the prefrontal cortex, a region responsible for impulse control and decision-making. The integrity of white matter is also compromised, as communications among brain regions are greatly hindered. Meth’s ability to easily cross the blood-brain barrier rapidly due to its lipophilic nature enhances its neurotoxicity which can lead to neuroinflammation, cerebral atrophy, and impaired motor function. Some genes and epigenetic factors, such as variations in genes related to dopamine and DNA methylation changes, can predispose individuals to addiction and are able to be passed on from one generation to the next, making some people more susceptible than others. Neuromapping techniques such as fMRI, diffusion tensor imaging, and magnetic resonance spectroscopy have revolutionized cerebral imaging and have been instrumental in visualizing the structural and functional changes in meth users’ brains. While there is some chance for the recovery of neurons with extended abstinence, oftentimes structural damage, particularly to the visual cortex in the occipital lobe, may be irreversible.  Other rehabilitative strategies such as cognitive training, exercise, and neuroprotective therapy also show promising results in restoring neuroplasticity and improving cognitive function. However, full cerebral recovery from methamphetamine-induced damage is still uncertain and studies are tentative. Understanding meth’s impact on the brain, its impact on heritable genes, and potential pathways for recovery is critical as we look to the future and develop more effective preventative and treatment strategies. 

 

Luvsannyam, Enkhmaa, et al. “Neurobiology of Schizophrenia: A Comprehensive Review.” Cureus, Apr. 2022, https://doi.org/10.7759/cureus.23959.

Editorial Staff. “How Do Drugs and Alcohol Affect the Brain and Central Nervous System?” American Addiction Centers, 17 Dec. 2024, americanaddictioncenters.org/health-complications-addiction/central-nervous-system.

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We would like to thank our teachers including Ms.Athwal and Ms. Okeith for their consistent support. We would also like to thank Ernest Manning High School for letting us register as representatives of them. We are truly in awe of how supportive our school community has been during this process. Additionally, we appreciate the immense contributions of researchers and scientists in the field of addiction who are continuing to make progressions with this incredibly important matter. We would also like to extend thanks to the CYSF staff, we are so appreciative to be a part of such an amazing program and continue to hold CYSF in the highest esteem.