Ms. Auld's Science Page



Memories formed under the influence of methamphetamine are harder to forget for the simple garden snail[1]. Scientists at Washington State University think this might help explain why it is hard for an addict to kick a drug habit – memory of the drug experience is very easily recalled and induces craving with very little prompting.

This lesson introduces amphetamines, which come in many forms and are used for many purposes. While much attention might be paid to methamphetamine (which like caffeine, is a methylated version of another mind-altering substance), the impacts of other forms of amphetamine are great and should not be overlooked. MOST amphetamines share a common structural basis upon which functional group modifications are made. But at least one notable amphetamine (Ritalin) looks quite different, but acts in similar ways. Amphetamines are stimulants that influence monoamine neurotransmitters, making one or more of them more available in the synapes.

Objectives

to understand what amphetamines ARE, where we find them, how we use them

to understand how amphetamines work at the level of the molecule, the neuron, the brain, and behavior.

to understand the reward pathway and how these particular drugs stimulates it.

to be able to relate the properties of amphetamines (in particular tolerance) to overdose potential.

to consider the impact of small chemical changes (methyl groups) on drug potency.

to understand how drugs have impact on both central and peripheral nervous systems and the impacts of peripheral nervous system stimulation.

to be able to relate these interacting molecules with the genes that encode them and develop an understanding of how genetic differences can influence drug experience.

to be able to weigh risks and benefits of this drug in a knowledgeable way that assists in wise decision making.

Before you begin!

Their ideas

Name as many forms of amphetamines as you can.

Why are amphetamines used medicinally (what do they treat)?

Is there an herbal form of amphetamine? Is there an endogenous form?

Amphetamines weighed heavily in one major world event – what was it?

Previously learned material

Amphetamines block dopamine reuptake. What is the impact of this on mood and neuron?

While most people administer amphetamines orally, some users have been known to grind up a tablet and insufflate it. What impact would this have?

One can speak of tolerance for the “therapeutic” effect of a drug or a side effect such as lethality. What would happen if only the therapeutic effect showed tolerance (this is true for amphetamines)?

Lesson: Amphetamines

Guiding Questions

1. What are different forms of amphetamines used for and how do they differ from each other in their impacts?

2. Does an herbal drug give fewer side effects or dangers?

3. What are various ways a drug could increase the levels of a neurotransmitter in the synapse? Which of these ways apply to amphetamines?

4. How does tolerance influence the therapeutic dosage and therapeutic index of amphetamines?

 Key Terms

• Insufflation

• Endogenous

• Methyl

• Phenylethylamine

Activity One: Web Site Review

Please review the Web sites below. Guiding questions precede each web site.

1) Visit the National Institute on Drug Abuse (NIDA)'s page on methamphetamine.

Guiding questions:

What molecule(s) are affected by amphetamines? What symptoms are experienced by people using amphetamines? Why are amphetamines addictive?



2) At the "Mouse Party" simulation, choose the mouse with protruding ribs (can you guess why?).

Guiding questions:

Methamphetamine is similar to which neurotransmitter? How does that similarity relate to the impact it has on the synapse? How does methamphetamine influence the DIRECTION of recycling transporter function?



3) Please read the abstract associated with PubMed ID number "14686913"

Guiding questions:

Do you think adolescent use of amphetamines (a typical treatment for attention deficit hyperactivity disorder) influences the brain permanently? What features of neurons are altered when one uses amphetamines for a long time? What are the jobs of those neuron parts? What connection between dopamine and glutamate is suggested by this study? ()

4) And finally, take a quick look at the National Institute of Drug Abuse's page on methamphetamine.

Guiding questions: What schedule is methamphetamine? I is the "most dangerous". Why is it not schedule I? How is methamphetamine taken into the body? Which method of administration do you think is most addictive? What are some impacts of methamphetamine on brain structure and brain function?



Activity Two: What is amphetamine? Why do we use amphetamine?

"Amphetamine" means lots of different things to different people. This is in large part due to the variety of its forms. DEXTROAMPHETAMINE is a tablet form of amphetamine that has been used for a long time in the treatment of narcolepsy and obesity, and nearly as long to treat deficits in attention and focus (ADHD). Because amphetamines impact addition circuitries, alternative therapeutics are always being sought. Some are chemical derivatives of amphetamine (such as methamphetamine) and others are seemingly unrelated molecules such as Ritalin. One of the newest "non-stimulant ADHD medications is "Intuniv" whose chemical name is guanfacine. The manufacturers of this drug offer the following unhelpful information about how guanfacine works "Intuniv is thought to assist in the flow of information within the brain". But even Wikipedia (and other sites) tell us that guanfacine is an agonist of one type of norepinephrine receptor. Based on that, do you think Intuniv is a stimulant?

Herbal amphetamine comes in a couple of forms, found in plants growing in different regions of the world. MaHuang - or ephedra is an amphetamine found in Asia. Khat - sometimes spelled Cat or given a chemical name cathine - is an amphetamine found in Africa. Below are the chemical structures of dextroamphetamine, ephedra, and cathine. Examine these structures for noteworthy differences.

Review how to look at these chemical drawings. Remember where hidden "C" and "H"s are.

[pic][pic]

dextroamphetamine ephedra cathine (can't separate the two)

Amphetamines are used therapeutically for a number of conditions, many of which are no longer appropriate now that we know about amphetamine's addictiveness. They are used to treat ADHD, narcolepsy, and obesity.

Amphetamines are self-prescribed by some folks who work long hours (truck drivers).

And amphetamines are used as a euphoriant - to give one pleasure. Because of this, amphetamines are often used because a person has developed an addiction to them, making it very hard to quit.

TEST OF CONTENT

If amphetamines follow the same rule as xanthines with regard to the number of methyls, which amphetamine is most potent - dextroamphetamine, ephedra, or cathine? ephedra

Methamphetamine is an dextroamphetamine with an added methyl group. Do you think it's effects more closely resemble cathine or ephedra? one could argue either way. if it's just the methyls, then cathine might be a better match. But it also has a =O instead of a hydroxyl. If that is important, then ephedra is a better match.

Activity Three: How is Administered? How Much is Used?

How amphetamines are administered depends on who is using and which type of amphetamine they use. Ephedra and cathine were traditionally used as a tea. Amphetamine pills are also used orally. But one can take amphetamine by insufflation, by injection, and even by smoking it.

Therapeutic dosages vary quite a bit. It is typical that a physician will start by prescribing 5 mg per day. That dosage can go as high as 60 mg per day, in part because an amphetamine user develops a steep tolerance to the drug, requiring more and more to get the same effect.

As one continues to use amphetamines, the difference between therapeutic dose and lethal dose narrows. While an initial therapeutic index of 100 is common, long-time users often are taking in a dose that is only different from the lethal dose by a factor of 10.

Activity Four: Bioavailability of Amphetamine

CYP2D6 metabolizes amphetamines with a half life of approximately 1 hour. This enzyme converts dextro-amphetamine into hydroxy-amphetamine, adding a hydroxyl group. But this is only one way in which amphetamine leaves the blood. Depending upon the conditions under which it is taken, often a large amount of amphetamine ends up, unaltered, in the urine. Curiously, the impact that amphetamines have on the brain peak before the blood level of the drug peaks. This suggests that tolerance can happen very quickly. Neurons bombarded with excessive amounts of amphetamine cope so that they become "immune" to further increases.

TEST OF CONTENT

If a patient is prescribed 30 mg of d-amphetamine in the form of Adderall per day, (not a time-release form which is very common), how much is left in the body after 3 hours? 3.75 mg. 15 mg after 1 hour, 7.5 after 2 hours, 3.75 after 3 hours.

Tolerance can happen because of increases in metabolic enzyme or decreases in receptor. Which mechanism would account for the rapid tolerance that leads to decreasing impact while blood level of amphetamine is still increasing? The latter, decreasing receptor binding. It cannot be increasing metabolic enzyme - because the amphetamine level would decrease if metabolic enzyme decreased.

Activity Five: Where Does Amphetamine Impact a Neuron? Then What?

Recall that on the axon terminals, neurotransmitter is released and then recycled through recycling transporters. These recycling transporters are usually specific for a particular neurotransmitter. And we think of them as working in one direction - from outside a neuron toward the inside (thus recycling expelled neurotransmitter back into the terminal).

Review the mouse party again - clicking on the methamphetamine mouse. Follow these "test of content" questions to see if you understand how amphetamines primary action impacts a neuron.

TEST OF CONTENT

Where on a neuron do amphetamines "bind"?

on the dendrite (post synaptic)

on the cell body

on the axon

on the axon terminal (pre-synaptic)

What molecule enables amphetamines to enter a cell?

dopamine transporter

dopamine receptor

dopamine

Upon entering, what happens to dopamine?

it is recycled back into the cell

it leaves the cell

it is metabolized

it is converted into amphetamine

Dopamine in the synapse does what when a person uses amphetamine?

it is quickly recycled

it is quickly metabolized

it stays in the synapse due to blocked recycling transporters

it stays in the synapse due to inhibited metabolic enzymes

When you know the answers to the above questions, proceed with this activity (you're almost done).

While it is true that the primary impact of amphetamine on a neuron is to stimulate dopamine release and block it's reuptake, there are other affects. The second major affect is for norephinepherine recycling to be inhibited. Thus TWO monoamines, dopamine, and norepinepherine, remain in the synapse abnormally long when a person uses amphetamine.

Activity Six: Why Are Amphetamines Addictive?

It might already be clear to you that amphetamines ARE addictive (you never hear of a casual methamphetamine user) and you are probably already prepared to understand WHY amphetamines are addictive. Their addictive power comes from their ability to stimulate the reward pathway. Like cocaine, this happens in part because of blockage of dopamine recycling. But unlike cocaine, there is also elevated dopamine release and blockage of norepinepherine recycling. So the impact of amphetamines is wider and if used in a form that delivers the drug to the brain rapidly (insufflation or injection) the onset of the high is so rapid that the intensity is very great.

Many experts rate methamphetamine as an equal to nicotine in addictiveness. Some say more (they favor ratings that focus on the quickness of compulsive use or the lengths an addict will go to for a "fix"). Others say less (they focus on the success rate of breaking the addiction cycle).

TEST OF CONTENT

Come up with TWO reasons for methamphetamine being more addictive than dextro amphetamine. speedier to the brain (injected) and extra methyl group makes it more intense

Activity Seven: Does Amphetamine do ANY Good?

Therapeutic uses for amphetamines include treatment of narcolepsy, obesity, and ADHD, as mentioned in activity two. It might surprise you to think that amphetamines could help a person focus. One associates the stimulation of dopamine and also norepinepherine as being exciting, not calming and focusing. While the answer to why amphetamines help focus an ADHD patient aren't entirely clear, it has been shown that individuals with ADHD have less dopamine available, probably due to overactive dopamine recyclers. In the ADHD subject below, less red area suggests less dopamine receptor occupancy (which suggests less dopamine availability). Thus inhibiting dopamine recycling might diminish the deficit in focusing.

The image above comes from a study funded by the National Institute of Mental Health (NIMH). The color code shows presence of dopamine transporters. In non ADHD people, there are more transporters compared to people with ADHD.

In terms of treating narcolepsy or obesity, both wakefulness and appetite suppression are experienced on many stimulants, particularly so amphetamines. In the 1970's it was common to find dextro-amphetamine "chews" available to, and used commonly by, adolescents trying to lose weight. They were not particularly effective for long term weight loss and were also observed to have an addictive property. Additionally, many weight-loss amphetamines or amphetamine-like substances have been removed from the market due to serious health risks (see below).

Amphetamines are also used for "benefit" among people who want to/ need to stay awake, such as long-distance truck drivers. Methamphetamine was heavily used among soldiers in World War II (Japanese pilots and even Aldolf Hitler) both for its ability to put off exhaustion as well as its ability to make a person more comfortable taking serious risk.

Activity Eight: What are Amphetamine's Harmful Side Effects?

The stimulants may all act on different molecular targets and impact a variety of neurotransmitters and neurons, but they have a very similar constellation of side effects.

We haven't talked much about Ritalin - another ADHD stimulant that resembles amphetamines in function but not structure. Ritalin has been associated with 25 overdose deaths (19 of which were children) and dozens more heart attacks and strokes.

Recall from activity seven that treating obesity with amphetamines was relatively common. Well, also common among obese people is high blood pressure and vascular problems that go along with high blood pressure. Thus a stimulant, which, yes, reduces appetite, but also narrows blood vessel diameter will pose a serious health risk to obese users. For instance, FenPhen (the "phen" part is an amphetamine called phentermine) was studied in the 1980s and it was shown that 30% of its users had abnormal electrocardiograms! This caused it's removal from the market in the 1990's and a high number of law suits.

Even the herbal amphetamines are dangerous. Ephedra was a common ingredient in energy drinks and performance enhancing drugs. It was widely used in major league baseball and its use resulted in the death of one MLB pitcher, Steve Betchler. Ephedra became the first FDA banned herbal supplement in 2004. Among herbal supplements at the time, ephedra accounted for approximately 1% of the sales, but 64% of the serious side effects. Listen to the interview of a meth user at .

TEST OF CONTENT

After viewing the testimony of addicts who use amphetamines and try to quit, relate the withdrawal symptoms with the effects of the drug. What do you notice?

Amphetamines are particularly known for their ability to stimulate the sympathetic nervous system and make a user feel anxious, overwhelmed, worried. This is probably due to the structural similarity between amphetamines and norepinepherine.

Besides wakefulness, irritability, appetite suppression, and insomnia (all common side effects for stimulants), amphetamines have a serious psychological health risk. While it is debatable WHY amphetamine users are more likely to develop serious mental illnesses, including life-long psychoses, it is undeniable that they do. Some people think that people with mental health issues are more likely to choose to use and abuse amphetamines. Others think that users do not elevate already-existing risks of psychosis, but merely end up with symptoms earlier than they would have otherwise. Others strongly argue that the drug leads to psychosis in people who would not otherwise have mental health issues.

Long term amphetamine users are available for study thanks to the wide-spread prescription of amphetamines for ADHD. Recall the abstract we asked you to read, PMID 14686913. This abstract and other studies suggests that neurons respond to amphetamine use and excess dopamine stimulation by remodeling the neuronal wiring. This rewiring can look like many different things. It can mean a loss of receptor proteins on dendrites or permanent loss of dendrites. Connections that are normally present can be lost due to overstimulation.

One more side effect to add to the list, this one specific to methamphetamine. There are several studies that show long-term damage to the brain and even loss of brain cells among long term meth users. Some of these studies examine brain damage by looking for the presence of neuron-made chemicals which are reduced also during brain damage from stroke or Alzheimer's disease. One chemical, N-acetylaspartate (NAA) is reduced[2] Similarly, one can measure brain damage by assaying for chemicals made by glial cells in response to neuron damage. Choline and myoinositol are increased[3] are two glial-made chemicals that have been shown to be increased in situations of neuron damage and these are also increased in methamphetamine-exposed cells.

An admittedly limited study that followed 22 methamphetamine users for 10 years (and 21 matched subjects) showed that there was a significant loss of brain matter, of cells, among the meth users. There was 11% loss of volume in the limbic region and addicts experience craving, anxiety, and depression. There was an 8% loss of volume in the hippocampus, and addicts scored significantly worse on tests of memory. This study is from 2004, and its full citation is: P.M. Thompson, et al. (2004) Structural Abnormalities in the Brains of Human Subjects Who Use Methamphetamine. Neurobiology of Disease, volume 24(26), pages 6028-6034. But an easier way to find it is by using PubMed () and putting in the unique identifier, or PubMed ID number (PMID) 15229250. The article is also listed in our papers you might peruse if you have additional time and interest.

TEST OF CONTENT

What role do neuro glia have in the story of drugs and brain damage?

Some studies suggest that there are corrosive ingredients in meth that lead to dental problems, others suggest that these problems result from one of the other side effects listed. Which is that?

Ephedra is “herbal”. Many therefore claim it is natural and has no risk. For this and many other reasons, companies market and sold ephedra as a food supplement. Food supplements do not have to go through rigorous safety testing that drugs do. How, then, can they be determined to be UNSAFE?

Activity Nine: Individual Experience May Vary

The primary reason people will differ in their experience while using amphetamines is previous history of stimulant use, primarily amphetamine use. Amphetamine tolerance happens very fast and the increase in therapeutic dose rises particularly rapidly. Earlier we told you that the therapeutic index for amphetamines varied from 10 to 100. That range is much larger than can be accounted for or expected based on other contributers such as metabolic robustness or how healthy one is. The therapeutic dose rises quickly with minimal increase in lethal dose. Thus at the outset, a new user has a high TI (100) but as their dose increases, the TI narrows to 10.

While death can occur among users due to the cardiovascular effects of amphetamines, death can also occur easily in people who have attempted to quit but "fall off the wagon". A person who was used to using a high dosage as a regular user might return to that high dosage when resuming drug use, and this can have devastating consequences because the body is no longer accustomed to metabolizing the drug efficiently.

Our genes also influence our amphetamine experience. As with cocaine, differences in the CARTPT gene are known to alter one's response to amphetamine. The gene that encodes the dopamine transporter, called DAT, and the gene that encodes CYP2D6 will also influence our response to the drug. A gene that produces glial factor derived growth factor has also been shown to influence amphetamine response[4]

TEST OF CONTENT

A DNA “AmpliChip” has recently been approved to screen a person’s genotype for CYP2D6. Why might such screening be helpful? You will get one answer from this lesson, but visit the Wikipedia web site on CYP2D6 and see if you get a more thorough answer.

TEST OF CONTENT

Name one drug you would vehemently advise your Adderall-using friend to avoid. Back up your drug choice. Cocaine - both drugs will block dopamine recycling and using them together could lead to an alarmingly high level of dopamine in the synapse. Both are also known to lead to vascular problems associated with vasoconstriction.

Activity Ten: Reading

Required Reading

Liska - section 7.6 - 7.11 and questions 8 - 12.

Web sites







Videos

History channel videos on ancient drugs and illegal drugs



Supplemental Reading

Internet

(meeting abstract about studies looking at amphetamine-caused brain rewiring)

Thompson 2004 paper

TV series "Breaking Bad"

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[1] Kennedy, C. D., Houmes, S. W., Wyrick, K. L., Kammerzell, S. M., Lukowiak, K. and Sorg, B. A. Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis. Journal of Experimental Biology, 2010; 213: 2055-2065

[2] Ernst, T., Chang, L., Leonido-Yee, M. and Speck, O. Evidence for long-term neurotoxicity associated with methamphetamine abuse. A 1H MRS study. Neurology, 54:1344-1349, 2000.

[3] Ernst, T., Chang, L., Leonido-Yee, M. and Speck, O. Evidence for long-term neurotoxicity associated with methamphetamine abuse. A 1H MRS study. Neurology, 54:1344-1349, 2000.

[4] Y. Yan, K. Yamada, M. Niwa, T. Nagai, A. Nitta, and T. Nabeshima (2007) FASEB J 21, 1994-2004

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