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Amphetamines
Memories formed under the influence of methamphetamine are harder to forget
for the simple garden snail1. 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.
Lesson 18: Amphetamines
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.
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
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Amphetamines
Before you begin!
Your 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 18: 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:
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Amphetamines
What molecule(s) are affected by amphetamines? What symptoms are experienced by people
using amphetamines? Why are amphetamines addictive?
http://www.drugabuse.gov/DrugPages/Methamphetamine.html
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?
http://learn.genetics.utah.edu/content/addiction/mouse/
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?
(http://www.ncbi.nlm.nih.gov/pubmed/14686913)
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?
http://www.nida.nih.gov/infofacts/methamphetamine.html
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
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Amphetamines
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.
Cathine
ephedra
dextroamphetamine
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?
Methamphetamine is an dextroamphetamine with an added methyl group. Do you think it's
effects more closely resemble cathine or ephedra?
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.
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Amphetamines
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 timerelease form which is very common), how much is left in the body 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?
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"?
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Amphetamines
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.
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Amphetamines
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.
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 dextroamphetamine "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 longdistance 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.
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Amphetamines
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 (cannot make this link work-not
valid)
http://www.sciencentral.com/articles/view.php3?type=article&article_id=218392428.
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.
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Amphetamines
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 reduced2 Similarly, one can measure brain damage by assaying for chemicals made by glial cells in
response to neuron damage. Choline and myoinositol are increased3 are two glial-made chemicals that have been
shown to be increased in situations of neuron damage and these are also increased in methamphetamineexposed 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 (pubmed.org) 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?
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.
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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.
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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
response4
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
4
Y. Yan, K. Yamada, M. Niwa, T. Nagai, A. Nitta, and T. Nabeshima (2007) FASEB J 21, 1994-2004
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Amphetamines
Name one drug you would vehemently advise your Adderall-using friend to
avoid. Back up your drug choice.
Activity Ten: Reading
Required Reading
Liska - section 7.6 - 7.11 and questions 8 - 12.
Web sites
http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html
http://www.nida.nih.gov/infofacts/methamphetamine.html
http://www.drugabuse.gov/DrugPages/Methamphetamine.html
Videos
History channel videos on ancient drugs and illegal drugs
http://www.sciencentral.com/articles/view.php3?type=article&article_id=218392428
Supplemental Reading
Internet
http://archives.drugabuse.gov/meetings/wired.html (meeting abstract about studies
looking at amphetamine-caused brain rewiring)
Thompson 2004 paper
TV series "Breaking Bad"
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