The layman's neuropharmacology of amphetamine and the NDRIs ...

[Chip (OP)]

The layman's neuropharmacology of amphetamine and the NDRIs including catecholamine depletion

UPDATED: 24 July 2024

This evolving document is case for the drug holiday or a tolerance short-term reset, the pleasure curcuit / the reward pathway, meth/amphetamine's neurotoxicity (in drowning-type depth), risk mitigation and then near the end there is a copied and easy to read, simplified neuropharmacological review of methamphetamine, it's addiction mechanism, and then recovery.

There are some other items of interest right at the back.

* **What are the catecholamines and what do they do ?**

Catecholamines, which include **dopamine, epinephrine, and norepinephrine** monoamines, are the principal neurohormones or neurotransmitters and hormones that mediate a variety of the central nervous system functions, such as **motor control, cognition, emotion, memory processing, and endocrine modulation** and are produced in response to stress by the sympathetic-adrenomedullary axis and by the two small adrenal glands located just above the kidneys, respectively.

This is our **"flight-or-fight"** response to **danger** that probably developed to save us when we came in contact with a threat such as a tiger or some other predator -- our **heart rate increases, as does the pressure of blood** flowing into our major organs, breathing rate, **muscle strength, and mental alertness**, whilst reducing the amount of blood going to the skin, for **optimum performance** and probably so we didn't get slowed down by minor injuries.

In contrast to cortisol, which takes a few minutes to rise and which is considered to be an undesirable immune response in chronic stress situations, **catecholamines are released into the blood circulation within seconds** after a stressor (such as said tiger), so you can jump into action immediately.

(In organic chemistry, a catecholamine is the name of a group of compounds that contain a *catechol nucleus* (a benzene ring with two adjacent hydroxyl substituents) and an amine group)).

* **What are the sympathomimetic drugs and what do they do ?**

Sympathomimetic drugs or agents (adrenergic drugs and adrenergic amines) are stimulant compounds which in general **mimic the effects of endogenous agonists of the sympathetic nervous system** and act as agonists upon one or more adrenoceptors, as their pharmacological activity depends mostly on the subtype, location, and affinity to the adrenergic receptors.

Most of them, when consumed orally, are absorbed into the systemic circulation.

They are classified as **directly acting** (act directly on α or β receptors), **indirectly acting** (act by providing more norepinephrine and epinephrine (mediators of the sympathoadrenal system) to act on α or β receptors) or **mixed acting** (act by both mechanisms).

Most of these drugs are called external or exogenous **phenethylamines**.

These include **amphetamine**, substituted amphetamines, including **methamphetamine**, methylphenidate (**Ritalin**), MDMA (ecstasy),
cathinones, substituted cathinones,
**cocaine** (a relatively "balanced" short-lasting SNDRI (Serotonin+NDRI)), ketamine, marijuana, gamma hydroxybutyrate (and many others), and the herbs khat and ephedra, which encompass the only widely administered class of drugs that predominantly **indirectly activate to enhance the release of monoamine neurotransmitters, in this case principally catecholamines, as well as serotonin, frequently**, from the nerve terminals.

Despite the **close chemical resemblance** to the naturally occurring neurotransmitters, **these drugs are not able to activate the cellular receptors**.

Meth/amphetamine is an **indirect agonist** of dopamine, norepinephrine, and serotonin. It **competitively binds to the** VMAT-2 or Vesicular MonoAmine **Transporter** 2 (DAT, NET and SERT which all terminate signalling and **drive reuptake**), thus **causing sustained release** of dopamine, norepinephrine, and serotonin from the cytosol (intracellular fluid) into the synapse.

This is called **transporter-mediated reverse transport** or transporter reversal, which is a phenomenon in which the substrates of a membrane transport protein are **moved in the opposite direction to that of their typical movement by the transporter**.

(The dopamine transporter (DAT) is a **transmembrane protein** that is responsible for the reuptake of dopamine (DA) from the synaptic cleft and for the termination of dopaminergic transmission).

Cytosolic **MAO** or monoamine metabolism (specifically, catabolism) **provides an antioxidant defense in the brain** against oxidant- and free radical-induced damage by an enzyme called monoamine oxidase is involved in **removing the neurotransmitters** norepinephrine, serotonin and dopamine from the brain. You may be aware of MAOIs and amphetamines perform some degree of inhibition as well.

They also increase dopaminergic and noradrenergic inhibition of COMT or Catechol-MethylTransferase.

Finally, if you want to get really technical (and a bit freaky), many drugs, like Methamphetamine, **stimulate the [**TAAR1**](https://www.reddit.com/r/Drugs/s/TU7O7XOpMW) or Trace Amine-Associated Receptor which regulates DAT, and involves VMAT2, in shifting transporter **bidirectional** operation **from the uptake mode to a release mode** and **mediates drug abuse behaviours** (and is also referred to as the **God gene**, known to be implicated in **"spirituality"** 🙄).

In addition (and I did mention "really technical" so budding neuroscientists can "go deep"), amphetamine induced NET blockade in the prefrontal cortex, resulting in increased noradrenaline levels and alpha-1 receptor activation, appears to change the firing pattern of dopaminergic neurons in the ventral tegmental area that project to the nucleus accumbens.

Amphetamines also appear to affect the glutamatergic, **opioid** and cholinergic systems.

* **What's involved in the pleasure or "reward" circuits ?**

Drugs or alcohol can **hijack the pleasure/reward circuits in your brain** and hook you into **wanting more and more**. Addiction can also send your emotional danger-sensing circuits into overdrive, making you feel anxious and stressed when you're not using the drugs or alcohol.

**Deep within the brain** is a set of structures called the limbic system. The **limbic system contains the brain's reward circuit** or pathway. The reward circuit links together a number of brain structures that **control and regulate our ability to feel pleasure**, driving the desire to **repeat the stimulus**.

The crucial brain reward neurotransmitter activated and **released** by addictive drugs is **dopamine**, specifically in the “second-stage” ventral tegmental area to NAc or Nucleus ACcumbens link in the brain's reward circuitry.

However, recent studies suggest that **serotonin release may be involved**.

* **How do NDRIs work and how do they cause neurotransmitter depletion ?**

An NDRI (Norepinephrine or Noredrenaline and Dopamine Reuptake Inhibitor) such as Ritalin (methylphenidate) or the SNDRI cocaine, has a different mechanism from amphetamine as it doesn't release neurotransmitters (or signalling hormones), instead it **stops them from being recycled by inhibiting reuptake by the transporter** but still causing the same net effect of a higher extracellular concentration of neurotransmitters in the synaptic cleft (the space between the neuron's transmitting axon and the receiving neuron's dendrite) so there's still a whole lotta shakin' going on.

Unfortunately all that reuptake inhibition activity is too much for the brain/body so then it **reduces the amount of the transporters that are recycling or moving dopamine from synapse back to neuron** and too much of this, usually from using too much or too often, ends up with the same final conclusion as we see below 🥱.

* **What are the nerves, glia, neurons, neurotransmitters, synapses, receptors and what functions do they perform in the CNS and PNS ?**

The CNS (Central Nervous System) is made up of the **brain and spinal cord**, and is the body's processing centre. The brain controls most of the functions of the body, including awareness, movement, eating, thinking, speech, learning and the 5 senses, and are made of billions of **nerve cells called neurons that are information messengers**.

Neurons use electrical and chemical signals to **send and receive information** between different areas of the brain, as well as between the brain and the nerves of the spinal cord, and of the PNS (Peripheral Nervous System) which are all throughout the entire body.

The CNS and the PNS is also made up of another basic cell type called **glia**, gliocytes or neuroglia, that provide structure in the brain that **do not produce electrical impulses**. In some parts of the brain, there are many more glia than neurons, but neurons are the key players in the brain. Glial cells **support neurons and are called astrocytes and oligodendrocytes**.

Neurons **are born in areas of the brain that are full of neural stem cells**, or precursor cells and those stem cells have the potential to make most, if not all, of the different types of neurons and glia found in the brain. Neurons typically die each day and hundreds more are born in the hippocampus (memory) and olfactory bulb (sense of smell).

A neuron has **three basic parts**: a cell **body or soma** that can vary from 4 to 100 micrometers in diameter, two branches called an **axon** that is covered by the myelin sheath, and a **dendrite**.

Within the cell body is a **nucleus** which controls the cell’s activities and contains the cell’s genetic material. The **axon looks like a long extention or tail that sends messages/impulses** away from the cell body. A **dendrite is shorter extension that looks like the branch of a tree that receives incoming signals/messages** for the cell.

Depending on its location, a neuron can perform the job of a **sensory neuron, a motor neuron, or an interneuron**, sending and receiving specific chemicals called **neurotransmitters that communicate with each other across a tiny space called a synapse**, between the axons and dendrites of nearby neurons.

Most **neurotransmitters are synthesised or secreted from common cellular metabolites** by enzymes expressed specifically in neurons using the transmitter and **consist of small amine molecules (monoamines), amino acids, or neuropeptides**. A few other classical transmitters are acetylcholine, serotonin and GABA but they all **diffuse across the synaptic cleft**, and bind specific receptors in order to bring about changes in post-synaptic neurons.

The amino acid, **L-phenylalanine** easily crosses the BBB or Blood Brain Barrier, and is converted into **tyrosine**, which then converts into the catecholamines or **phenethylamines**.

For example, the catecholamine neurotransmitter, dopamine, is a **phenethylamine** (the body's "natural amphetamine") which is a monoamine or an **amine** (a nitrogen atom+a pair of electrons (that stand alone and are ready to bond)) connected to a **benzene ring** (a ring of six carbon atoms) by a two-carbon chains. This is the foundation upon which meth/amphetamine (**A**lpha-**M**ethyl-**PH**en**ET**hyl**AMINE**) is built, which hopefully is as interesting to you as it is to me 😋.

Their job is to **faithfully reproduce**, across the synapse, the **specific responses** that are evoked by the stimulation of pre-synaptic neuron which releases them from the axon vesicles (small sacs). Groups of vesicles is called an axon terminal, a **nerve terminal** or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz.

These responses are **reflected to the post-synaptic neuron**'s or effector cells, **dendrites**. They carry, boost and balance the signals released into the synaptic cleft but only acts for a very short duration, only minutes or even seconds.

After neurons are born, migrate to their appropriate positions, and extend dendrites and axons, neurons form **synapses** which are very small, narrow gaps of extracellular space, being approximately 20-40 nanometers (nm) wide. They allow pre-synaptic neurons to **convert an electrical signal (the spike or action potential) into a chemical signal in the form of neurotransmitter** release, and then, upon binding of the transmitter to the post-synaptic neuron's receptor, switching the signal back again into an electrical form, as charged ions flow into or out of the post-synaptic neuron.

The synapses initiate as nascent or new contacts that mature into functional but plastic synaptic connections and are eliminated under control of unknown.

Excitatory neurotransmitters  “excite” the neuron and cause it to “fire off the message,” meaning, the message continues to propagate so more **action potentials** are triggered whereas inhibitory signals (eg. GABA) work to cancel the signal so it gets blocked and doesn't pass any further.

When an action potential **propagates down the axon of a nerve and arrives at the axon nerve terminal it activates voltage-gated calcium ion (Ca2+) channels**.

This **impulse is sent or from the axon (or nerve fibre) to the receptors located on the dendrite**. Receptors are special molecules that receive and process the message. Most receptors are integral membrane proteins categorized as ligand-gated ion channels or G protein-coupled receptors (GPCRs).

Cellular **receptors are proteins** either inside a cell or on its surface which receive a signal.

(In normal physiology, this is a chemical signal where a protein-ligand binds a protein receptor. The ligand is a chemical messenger or neurotransmitter released by one cell to signal either itself or a different cell).

**After** receptor **binding**, the **neurotransmitter is immediately deactivated** by enzymes in the synaptic cleft; it **also may be taken** up by receptors in the pre-synaptic membrane **and recycled**, only to be retransmitted and **continue propagation**.

⚠️ But this excessive and unnatural activity of the nerve terminals causes **neurotoxicity**, considering that the phenethylamine, **amphetamine** has a half life of **4-6 hours**, far exceeding our internal or endogenous phenethylamine, **dopamine**, which is only **30 seconds**,  that our architecture was originally intended to support (more on this is explored further down) !

* **How do amphetamine type drugs work and how do they cause neurotransmitter depletion ?**

The neuron's vesicles are part of the nerve cell which store the neurotransmitters that are ready to be released and are destined to branch out to neighbouring neurons.

After this pre-synaptic release they are shut by means of **kiss-and-run fusion** 😘 .

These **pre-synaptic** or sending **vesicles** that are found in the many neurons in the 🧠 **need to recover from synaptic fatigue** or short-term synaptic depression, which is an activity-dependent form of short term synaptic plasticity that results in the **temporary inability of neurons to fire**, and are therefore unable to transmit an input signal.

They get **tired from the persistent stimulation** when it's occurring at a high enough frequency and with enough strength, **neurotransmitters will be released at a faster rate than transporter reuptake can recycle them which will ultimately deplete** them until there are no longer readily releasable vesicles and a signal can no longer be transmitted, so it's no wonder the signal ain't going nowhere and neither are you ... 🛌 💤

* **The "drug holiday" and recovery**

It's now time for a drug holiday, which is a break in all stimulant use for **at least 5-7 (amph) to 10-14** (meth) days.

There are a number of safe and natural ways to boost neurotransmitters. Lifestyle habits like exercise, giving and receiving affection, and spending time outdoors can all increase serotonin and dopamine. Supplements for neurotransmitters are also helpful, such as phosphatidylcholine (PC), B and D vitamins etc., as you'll see further down.

Create exciting daily routines. Incorporate fun activities into your daily routine, even if they are mindless activities.

Also:
•focus on perfecting your **sleep schedule**
•improve your **diet**
•exercise
•practice mindfulness
•listen to music

** *The synthesis and regulation of neurotransmitters**

There are many nutrients that are essential to this critical process, including amino acids (especially the precursors tryptophan and L-phenylalinine OR L-tyrosine or NALT for the catecholamines and serotonin), °CDP-choline, vitamin B, C vitamins (especially B6, B12, and folate), large amino acids (i.e., valine, leucine, isoleucine), zinc, iron, omega-3 fatty acids, and vitamin D.

Studies in animals suggest that **CDP-choline** supplements increase dopamine receptor densities and can ameliorate memory impairment. In Parkinson's disease, for example, CDP-choline may increase the availability of dopamine. Daily doses under 3.5 grams are considered to be safe.

There are also certain foods that are known for their overall benefits for the brain. One example is tea, most likely due in part to the amino acid L-theanine, which influences dopamine and GABA levels in the brain.

More about this can be found out about [eating for neurotransmitter repletes](https://deannaminich.com/eating-for-your-neurotransmitters/#:~:text=There%20are%20many%20nutrients%20that,phenylalanine)%2C%20zinc%2C%20iron%2C).

**Did the different mechanisms make a difference ?**

If you were wondering if made any difference to cocaine and methamphetamine users, then no, not much as they share similar neuropsychological profiles.

However, cocaine appears to be more associated with working memory impairments, which are typically frontally mediated, while methamphetamine appears to be more associated with memory impairments that are linked with temporal and parietal lobe dysfunction.

● **What is neurotoxicity, what damage does it do and how does it work ? Using methamphetamine as an example**

Withdrawal may cause the user to have an impaired ability to experience pleasure (anhedonia), slipping into a deep depression all of which motivates the user to keep repeating the experience and even increasing the dose, all of which causes neurotoxicity when used non therapeutically.

Symptoms of dopamine deficiency (low dopamine levels) may include:

•You lack motivation, “the drive.”
•You're tired.
•You can't concentrate.
•You're moody or anxious.
•You don't feel pleasure from previously enjoyable experiences.
•You're depressed; you feel hopeless.
•You have a low sex drive.

Methamphetamine is known to have a **neurotoxic effect on serotonin** neurons, which have been implicated in the regulation of mood, anxiety, and aggression.

Normally, a neurotransmitter is either destroyed by enzymes, such as acetylcholine esterase, or is reabsorbed into the terminal button of the presynaptic neuron by reuptake mechanisms and then recycled.

Most neurotransmitters are recycled rather than degraded. Recycling might take a few milliseconds. Degrading can take 20 to hundreds of milliseconds or even hours, depending on the neurotransmitter.

Neurotoxicity describes the damage to neurons that involve increases in intra and extracellular concentrations of dopamine which sets off a cascade of events including **oxidative stress** or damage to **axon terminals**, **neuroinflammation**, and **excitatory neurotoxicity**, as described below.

Increases in the neurotransmitter glutamate (the major excitatory neurotransmitter in the brain) and calcium often as a result of the **neurons being overly excited and continuing to fire** to the point of actually damaging the system. If not modulated, this can result in significant damage throughout the central nervous system.

Oxidative stress is further increased because of depletion of antioxidant enzymes due to methamphetamine itself.

**Oxidative stress refers to elevated intracellular levels of ROS** or Reactive Oxygen Species, that cause **damage to lipids, proteins and DNA**. It can also be detrimental to cardiac function.

Methamphetamine abuse causes **neuronal apoptosis, or rapid cell death** in humans. This can result in a spectrum of mild to moderate neurocognitive disorders that may progress to dementia.

**Reward system damage happens here**

Methamphetamine **damages dopamine and serotonin nerve terminals** by way of alterations but not in the cell bodies themselves.

The **nerve terminal** is a specialized region of a neuron, separated from the neuronal soma by an **axon** that can be exceedingly long, whose function is to release the neurotransmitter when stimulated by an electrical signal carried by the axon.

Neurotoxicity causes significant damage to the **dendrites** of neurons. They are the receiving portions of the neurons that receive the chemical signals from other neurons. This damage prevents the neurons from communicating effectively and can affect a number of cognitive and motor functions.

There is growing evidence that **neuroinflammation** also plays an important role in the etiology and pathophysiology of brain dysfunction induced by Meth abuse -- abnormalities of the **microglia and astrocyte**, which are **critical mediators of CNS neuroimmune pathology**, have been observed. The bidirectional communication between neurons and glia is essential for the homeostasis and biological function of the CNS while activation of glia induces the release of cytokines and chemokines during pathological conditions, which will affect the neuron–glia interactions and lead to **adverse behavioral consequences**.

**What about the neurons ?**

~~in most parts of your brain, the set of neurons you're born with is what you've got for life — just like your fingers and toes, if you lose any, they're not going to recover and are never coming back. The body does have ways to encourage healing after a brain injury, but they are extremely constrained.~~

After the damage of brain cells or neurons in a certain area of the brain, the surviving brain cells adapt to compensate for the lost cells. This ability of the brain is known as neuroplasticity, which helps the brain to repair itself.

**Neurons can actually regenerate** using a really unique method if an area of the brain gets damaged – we call this method **neurogenesis**.

Neuronal death is normal during nervous system development but is abnormal in brain and spinal cord disease and injury. Both **apoptosis and necrosis** are types of cell death. They are generally considered to be distinct forms of cell death.

Although thousands of new brain cells called neurons are produced each day in adults brains, only a small percentage of them survive. The cells that die are consumed by scavenger cells called phagocytes.

NB: This may or may not be a bad thing:

* Meth kills Glial Cells 

> Glial cells are a significant part of the central nervous system. They’re responsible for signaling capacities, fighting infections, and developing myelin cells. 

The use of methamphetamine **damages and kills these cells** throughout areas in your brain, but especially in your prefrontal cortex which is the part of the brain that allows you to **pay attention, think abstractly, make judgment calls, and make plans**.

> Therefore there will be **more functional mistakes** due to the lack of effective communicators in the central nervous system.

* Meth decreases myelin cells

> Myelin cells, also called white matter, play an important role in signaling between neurons. These cells are responsible for many basic functions of the central nervous system. 

* Affects microglia cells

> They are responsible for cleaning up damaged brain cells and fighting infection. Meth has been shown to increase the activity of microglia, leading to the destruction of healthy brain cells.

⚠️ I suggest that the above mentioned **Glial damage may be caused by most stims** but to varying degrees.

* Mice testing

Loss of cells in the hippocampus and cortex could damage memory, cognitive function, and decision-making capacity

Loss of striatal cells could lead to serious movement disorders that resemble tardive dyskinesia and Huntington's chorea.

Nerve damage may result from activation of the molecular machinery that is involved in apoptosis. The strongest evidence that **methamphetamine unleashes widespread apoptosis** in animals came in a recent study that showed the drug caused DNA fragmentation and loss of nerve cell bodies in the striatum, the hippocampus, and the frontal cortex of mice brains.

* **Synopsis: What is meth-induced neurotoxicity ?**

Long-term methamphetamine use can induce neurotoxic effects through oxidative stress, mitochondrial functional impairment, reticulum stress, the activation of astrocytes and microglial cells, axonal transport barriers, autophagy, and apoptosis.

**Neurotoxicity reference(s)**

* The Role of Biogenic Amine Transporters in Trace Amine–Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity

> Methamphetamine (MA) impairs vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function and expression, increasing intracellular DA levels that lead to neurotoxicity. The trace amine–associated receptor 1 (TAAR1) is activated by MA, but when the receptor is not activated, MA-induced neurotoxicity is increased.

* **Meth's neurotoxicity**

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750185/

**What about MDMA's neurotoxicity ?**

This is very different as the toxicity is caused by MDMA's **catechol metabolites**, **α-methyldopamine** (α-MeDA) and **N-methyl-α-methyldopamine** (N-Me-α-MeDA), and not by the sustained serotonin.

* **Some excellent nueroprotectants**

**NAC** or N-Acetyl-Cysteine, is a glutathione substrate that can readily be taken up by neurons. Glutathione in neurons acts as a free radical scavenger (an antioxidant) that protects the cytochrome oxidase system in mitochondria, and **improves neuronal regeneration**.

Others are:

Selenium,
Melatonin,
Vitamin C,
Selenium,
Memantine,
++very potent: Mentantine+Donepezil,
Antipsychotics

**References for nurotoxicity and other damage**

* Neurologic manifestations of chronic methamphetamine abuse

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451/#:~:text=With%20repeated%20use%20in%20both,dopamine%20and%20serotonin%20nerve%20terminals.

* MOLECULAR DESCRIPTION OF NERVE TERMINAL FUNCTION

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762394/#:~:text=The%20nerve%20terminal%20is%20a,signal%20carried%20by%20the%20axon.

* Effects of Crystal Meth on the Brain and Central Nervous System

https://americanaddictioncenters.org/meth-treatment/effects-on-the-brain-and-cns

* The Crosstalk Between Neurons and Glia in Methamphetamine-Induced Neuroinflammation

https://link.springer.com/article/10.1007/s11064-021-03513-9

https://socalsunrise.com/what-does-meth-do-to-your-brain/

https://www.therecoveryvillage.com/meth-addiction/meth-affect-brain/

* Methamphetamine Brain Damage in Mice More Extensive Than Previously Thought

http://www.dronet.org/sostanze/sos_info_art.php?artid=43&titolo=Amfetamine%20Metamfetamine&codice=3

https://biology.stackexchange.com

* **Meth and the body** (a stolen but fabulous overview)

One of the questions we often get is, why do people take this drug?

And people start taking drugs for a whole variety of reasons. Curiosity. Peer Pressure. In the case of methamphetamine some people take it because they know they can lose weight with it.

But after they've taken the first dose for whatever reason, why they continue to use it is pretty common. It's because they like what it does to their brain. They like how it feels.

Methamphetamine effects the centers of the brain that **control judgment, control reward, control temptation and control memory**. The most important one probably are the reward centers of the brain. When, when that part of the brain is stimulated dopamine's released, and you experience that as pleasure. Under normal circumstances those responses occur for naturally occurring rewarding events.

Similarly if you put a rat, a male rate in a box and you give him access to a receptive female, and you allow them to have **sex**, at the point where they experience orgasm you get a huge release of dopamine. You see an increase of **about 200 units**. This rush is what feels good and what is experienced is pleasure. Go to the graphic at the source article http://www.pbs.org/wgbh/pages/frontline/meth/body/methbrainnoflash.html to see the slide which of course illustrates the principle that **one orgasm equals two cheeseburgers**.

Now drugs of abuse release dopamine. **Alcohol**, for example, produced a release of dopamine from **about 100 units to about 200**. You get a **similar magnitude of an effect with nicotine**. **Cocaine** produces a huge release of dopamine, from 100 units to **about 350 units**, however the mother of them all is methamphetamine. **Methamphetamine you get a release from the base level to about 1250 units**.

**The reward system hijack**

A tremendous increase of dopamine. This produces an extreme peak of euphoria that people describe as something like they've never experienced and they probably never have experienced before because the brain really isn't made to do this. And that's why people will be attracted to it and want to take it over and over and over again. They want to produce that response.

Over time doing this to the brain and having it feel good changes the way the brain works. Part of what we've learned about addiction is that addicts, after they've used drugs, have different brains than they did before they used drugs.

**Observed changes the result from being addicted**

The units that are changed are these, the neurons. Dendrite, cell body, axon, terminal. Dopamine has its effect here at the terminal. Dopamine is stored in the nerve terminals in these, in these little sacs called vesicles. Sit there waiting until a nerve impulse comes down from the, the neuron, causes these to move to the cell wall and release their dopamine.

These little dopamine guys get released, they float across the synapse, they attach on the receptor and they cause the downstream neuron to fire. If that goes on in the reward centers of your brain that feels good They sit here for a few microseconds, they're released, and they're taken back in and recycled.

That's how the **reward or pleasure system** is supposed to work. You have this recycling where these mechanisms called reuptake pumps pull them out of the synapse and bring dopamine back in to be reused.

When you take **cocaine**, the only effect cocaine has is to sit on these reuptake pumps and block them. That means that as this cell fires and releases dopamine into the synapse dopamine accumulates because this ting has been deactivated. Dopamine accumulates causing this cell to fire and fire and fire way longer than it's supposed to because the dopamine isn't being pulled out of the synapse. And in fact cocaine will sit here for an hour or two causing this big accumulation of dopamine and this extended feeling of pleasure.

Now **methamphetamine** takes it one step further. Methamphetamine actually will sit here for eight to 12 hours causing this build up of dopamine for a much longer period so you experience this positive feeling for a longer period of time plus methamphetamine is actually taken into the terminal and **destroys the nerve terminals**.

Now luckily for meth users they almost all regrow; however the bad news is they take quite sometime and for months meth users are feeling the absence of this reward because the reward center of the brain has essentially been damaged. Other areas of the brain are also effected, so go to the graphic at the source article http://www.pbs.org/wgbh/pages/frontline/meth/body/methbrainnoflash.html

This is an MRI of the human brain done here at UCLA and this shows the **judgment center** of the brain in the prefrontal cortex. This is the brain of a meth user who's about five days sober and this blue area represents a reduction in normal activity, a reduction in blood flow. In essence, this part of the brain is shut off and for meth users who are in early recovery, they really don't have the ability to make good decisions.

You have this sort of worst-case scenario. You have a brain that is not producing reward, you're having a lotta craving because you want to feel better, and you have the part of the brain that controls judgment not working, and so individuals do stupid things that end up with them relapsing and going back to using. It's a wonder any meth users ever get better, but in fact they do.

* An investigation into how and why meth use spiraled out of control and became the fastest-growing drug abuse problem in America

> **Meth and the body**

http://www.pbs.org/wgbh/pages/frontline/meth/body/methbrainnoflash.html

**Some random related topics**

* Drug Surprise: Meth Makes You Feel Almost As Cuddly as Ecstasy

https://healthland.time.com/2010/12/20/drug-surprise-meth-makes-you-almost-as-cuddly-as-ecstasy/

* **Meth and moral judgment**

Research has shown that stimulant users often find it **difficult to identify other people’s emotions, particularly fear, and to show empathy**.

These aspects play an important role in moral decision making. Other studies have pointed to structural and functional abnormalities in especially the frontal regions of their brains among stimulant users. These areas are engaged when moral judgments have to be made.

Compared to the non-users, the regular stimulant users had abnormal neural activity in the frontal lobes and limbic regions of their brains during moral processing.

Specifically, **lifetime stimulant users** showed **less activity in the amygdala**, a group of neurons in the brain that helps to **regulate and understand emotions**.

The researchers also observed a relationship in the level of engagement of the anterior cingulate cortex: the longer people had been using stimulants, the less activity in this region, which is an area of the brain that coordinates reinforcement, effect and executive action needed in **moral decision making**.

* Brain scan study uncovers why cocaine and methamphetamine may impair moral judgment

https://www.psypost.org/cocaine-meth-may-impair-moral-judgment/

**Methamphetamine *vs* Dex/amphetamine**

> Methamphetamine released dopamine in the prefrontal cortex *less* effectively than *d*-amphetamine.

**Larger methamphetamine doses** (e.g., 2.5–10 mg/kg) increased locomotor activity to a **greater extent than d-amphetamine** in mice, whereas smaller doses (e.g., 0.5–1 mg/kg), made them equipotent at activating locomotion.

In the *in vitro* expression system, DAT-mediated whole-cell currents were greater for METH stimulation than for AMPH. At the same voltage and concentration, **METH released five times more DA than AMPH** and did so at physiological membrane potentials.

At maximally effective concentrations, METH released twice as much Ca2+ from internal stores compared with AMPH.

* Comparison of intranasal methamphetamine and d-amphetamine self-administration by humans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475187/

* Amphetamine and Methamphetamine Differentially Affect Dopamine Transporters in Vitro and in Vivo

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631950/

* Study suggests the brain's reward system works to make others happy, not just ourselves

https://medicalxpress.com/news/2024-04-brain-reward-happy.amp

**References**

* Brain Basics: The Life and Death of a Neuron

https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-life-and-death-neuron#:~:text=Neurons%20are%20nerve%20cells%20that,were%20ever%20going%20to%20have.

* Mechanisms of neurotransmitter release by amphetamines

https://pubmed.ncbi.nlm.nih.gov/15955613/#:~:text=Amphetamine%20and%20substituted%20amphetamines%2C%20including,principally%20catecholamines%2C%20by%20a%20non%2D

https://en.m.wikipedia.org/wiki/Neurotransmitter

https://en.m.wikipedia.org/wiki/Synaptic_vesicle#:~:text=After%20release%20of%20the%20neurotransmitter,kiss%2Dand%2Drun%20fusion.

* NDRI neurotransmitter depletion

https://www.reddit.com/r/ADHD/s/kiMvBqHxP3

* What are amphetamines and how do they work in the brain? 

https://academic.oup.com/book/6619/chapter-abstract/150624121?redirectedFrom=fulltext

https://www.vedantu.com/neet/difference-between-axon-and-dendrites

https://en.m.wikipedia.org/wiki/Sympathomimetic_drug#:~:text=Sympathomimetic%20drugs%20(also%20known%20as,cardiac%20contraction%2C%20and%20blood%20pressure.
https://en.m.wikipedia.org/wiki/Sympathomimetic_drug#:~:text=Sympathomimetic%20drugs%20

* Long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751231/

The layman's neuropharmacology of amphetamine and the NDRIs including catecholamine depletion