Victoria Semple
VBSC330
April 12, 2013
Dr. Glick
CYP2D6 Polymorphisms and Methamphetamine Dependency
Cytochrome P450 2D6 is an iconic example of genetic polymorphism and is
part of the cytochrome P450 family of the phase-1 drug metabolizing enzymes.
Approximately 20-25% of clinically used dugs are metabolized by CYP2d6 including
antidepressants, antiarrhythmics, and analgesics.The polymorphism of the enzyme
results in poor, extensive, or ultrarapid metabolizers of CYP2D6 drugs. The variations
may result from point mutations, single base-pair deletions or additions, gene
rearrangements, and deletion of the entire gene. The poor metabolizers are homozygous
for the recessive allele, which code for decreased enzymatic activity. They may also code
for a deletion of CYP2D6 gene. Extensive metabolizers are heterozygous or homozygous
for the wild-type trait, while the ultrarapid metabolizers may have several copies of the
gene; possibly up to 13 (Mcleod). In the clinical setting, a patient’s CYP2D6 type can
have major implications regarding drug treatment and dose. The poor metabolizers are
more likely to have adverse reactions to drugs that are substrates of CYP2D6. An
example of this is codeine being metabolized to morphine by the CYP2D6 catalysis. Poor
metabolizers will not feel expected effects from a standard dose. On the other hand, an
ultrarapid metabolizer may experience an overdose from a standard dose of codeine
because it is converted to morphine very quickly, elevating the plasma levels to a great
extent. Extensive and ultrarapid metabolizers may fail to experience therapeutic benefits
from drugs activated by CYP2D6 such as standard antidepressant doses (Mcleod).
Although many drug interactions and effects of the CYP2D6, there are still several that
are still being researched. In the case of amphetamine, the compound is metabolized in
the liver and does involve the CYP2D6 and in vitro experiments with human microsomes
indicate minor inhibition of CYP2D6 by amphetamine although there is not enough
information to make conclusions about the interaction with other drugs or the various
metabolism types (Parker).
Methamphetamine is part of the amphetamine class and is an extremely
addictive stimulant that is very closely related to amphetamine itself. It is a white
odorless powder that is often illegally self-administered via intranasally, injecting,
or heating it in rock (crystal) form and inhaling the vapors. Users experience a
sense of euphoria, alertness, decreased appetite and enhanced self-esteem. Despite
the common abuse of this drug class, some amphetamines may be therapeutically
used in low doses and are legally manufactured by pharmaceuticals. The
pharmacological responses of the drugs vary specific drug type, dose and route of
administration.
Victoria Semple
VBSC330
April 12, 2013
Dr. Glick
Chemistry
Structurally, methamphetamine and amphetamine are very similar as they are both
chiral compounds and rings. Amphetamine can exist as two enantiomers,
dexamphetamine and levoamphetamine. Dexamphetamine is more “typical”
because it is more centrally active. Amphetamine is the parent compound of the
amphetamine structural class and has several psychoactive derivatives including
methamphetamine, which is the N-methylated version and MDMA (ecstasy).
(PubChem). Amphetamine comes from phenethylamine, which is a natural monoamine
alkaloid that functions as a neurotransmitter and is biosynthesized from phenylalanine by
decarboxylation. The further methylation of amphetamine with another methyl group, the
nitrogen atom produces methamphetamine.
Pharmacology
Drug Targets
There are a few drug targets for methamphetamine. The sodium-dependent
dopamine transporter acts as a negative modulator and inhibits the dopamine
action by its high affinity sodium-dependent reuptake into the presynaptic
terminals. The sodium-dependent serotonin transporter and sodium dependent
noradrenaline transporters block serotonin and noradrenaline, respectively, by
blocking the high affinity sodium-dependent reuptake into presynaptic terminals.
Methamphetamine also acts on the synaptic vesicular amine transporter by
inhibiting the ATP-dependent vesicular transport of biogenic amine
neurotransmitters that is responsible for pumping dopamine, norepinephrine,
serotonin and histamine into synaptic vesicles. Amphetamines act on these same
targets.
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April 12, 2013
Dr. Glick
Mechanism of Action
The amphetamine class mainly acts on the dopamine transporter and has
three major effects which includes depleting the vesicular dopamine, reverse
dopamine transporter by efflux of dopamine back into synaptic cleft, and inhibiting
the uptake of dopamine. As soon as amphetamines are in the presynaptic nerve
terminal, the vesicular monoamine transporter subtype 2 proteins (VMAT-2)
transport the amphetamines into dopamine containing vesicles. In exchange, the
VMAT-2’s release dopamine into the cytosol (Rothman). The normal VMAT-2
function is to move monoamine neurotransmitters across their concentration
gradient and into the synaptic vesicles for storage. Once the vesicular dopamine
stores are depleted, there will be a greater concentration of dopamine in the
presynaptic terminal than in the presynaptic cleft. A dopamine efflux into the
synaptic cleft is the result of the reverse transport of dopamine by the dopamine
transporter.
This allows for an increased concentration of extracellular dopamine in the
mesolimbic reward pathway, particularly in the striatal nucleus accumbens of the
limbic system. In addition alertness, energy and wakefulness, the drug action
involves activating the cardiovascular system. The release of norepinephrine from
sympathetic nerve endings causes the increased heart rate and blood pressure
(Kish).
ABUSE
Mechanism of Abuse
The link between “drug-liking” and “drug-craving” is currently unknown but
research suggests that due to the low levels of striatal dopamine in recreational
users (high doses), there is a depletion of dopamine. When a user experiences these
low dopamine levels, they have cognitive impairment, and withdrawl symptoms
such as panic attacks, drug cravings, weight gain, increased appetite, irritability,
irregular heartbeat and depression. In a study conducted on mice, Dr. Nigel Bamford
concluded that “repeated use of methamphetamine causes adaptations in the brain”
and only by re-introducing the drug can this be reversed. The common treatment for
addiction involves giving the patient less and less amounts of the drug would not
work in treating a withdrawl because it would not reverse the adaptation of the
neural terminals in the brain (ScienceDaily)
Potential for Addiction
Despite its high potential for addiction and abuse, methamphetamine and
other amphetamines from the amphetamine class have therapeutic purposes. When
taken in small doses, the drug helps control the symptoms of Attention Deficit
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Dr. Glick
Hyperactivity Disorder (ADHD), severe obesity, and narcolepsy. Currently, the
specific mechanism of action that produces the beneficial behavioral changes in
children receiving methamphetamine is not yet discovered.
Long Term Use
Serious problems with mental and physical health can occur as a result of the
long-term use of amphetamines and methamphetamines. When using these drugs
regularly, it is common for the user to experience an amphetamine psychosis, which
includes symptoms such as paranoia, hallucinations and bizarre or violent behavior.
In addition to the psychosis, there have also been various structural and chemical
changes to the brain in some methamphetamine users. In a study published in “The
Lancet”, Thomas Ernst used proton magnetic –resonance spectroscopy to study
several cerebral metabolites in 26 methamphetamine users who had not used the
drug between 2 weeks and 21 months and also 24 adults with no drug history. It
was reported that concentrations of N-acetyl aspartate, a neuronal marker, showed
a 5% decrease in the basal ganglia and a 6% decrease in the frontal white matter in
the brains of users (Larkin). It was concluded that because dopaminergic neurons in
the basal ganglia were affected, methamphetamine users are much more likely to be
predisposed to Parkinson’s disease than non-users.
Methamphetamine exposure in high doses damages dopaminergic neurons in
the substantia nigra, resulting in a great loss of dopamine in the striatum.
Biochemical and neuroimaging studies in human methamphetamine users have
shown decreased levels of dopamine and dopamine transporter. (Granado).
However, at low doses, methamphethamine and amphetamine may be “preferential
for serotonin neurons, and that dopamine neurotoxicity may not occur with low
dose regimens used to treat ADHD” as stated by Ernst in The Lancet.
In another study, it was observed that dopamine transporter function was reduced
for at least 11 months in the basal ganglia in addition to reduced glucose
metabolism. The former users also experienced slow motor and memory
impairments. A significant reduction in dopamine transporter density in the basal
ganglia and nucleus accumbens were present long after stopping the drug use,
suggesting injury to the dopamine neurons as evidenced by the reduction in
dopamine receptors and brain metabolism in dopamine innervated regions.
Methamphetamine abuse has serious dangers associated with it. Reductions
of dopamine function, activity, and quantity are seen in striatal. frontal cortical, and
nucleus accumbens. These conditions lead to srtuctual damage in the brain and
chronic psychotic states that may include behavioral problems that may be a
challenge to treat such as sexual function, sleep, depression, locomotion issues,
schizophrenia and frontal lobe executive functions. (Julien)
In conclusion, the CYP450 enzyme metabolizes many drugs, including the
amphetamines, which are a highly addicting drug. It is still unknown how the
polymorphisms of CYP2D6 affect the users experience of amphetamines. The
Victoria Semple
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Dr. Glick
mechanism of dependency is complex and very limited in treatment options due to
the long term and possibly permanent decrease in dopamine neurons.
Works Cited
Victoria Semple
VBSC330
April 12, 2013
Dr. Glick
"The Pharmacology of Amphetamines." The Pharmacology of Amphetamines. N.p., n.d.
Web. 12 Apr. 2013. <http://www.mongboards.com/Pharmacology/Amphetamines.htm>.
University of Washington (2008, April 10). Methamphetamine Addiction Mechanism Discovered,
Explains Why Cravings Last So Long. ScienceDaily. Retrieved April 12, 2013, from
http://www.sciencedaily.com/releases/2008/04/080409120619.htm
Julien, Robert M., Claire D. Advokat, and Joseph E. Comaty. A Primer of Drug Action: A
Comprehensive Guide to the Actions, Uses, and Side Effects of Psychoactive Drugs. New
York: Worth, 2008. Print.
Larkin, Marilynn. "Methamphetamine use could Lead to Long-Term Brain Damage." The Lancet 355.9210
(2000): 1162-. ProQuest. Web. 12 Apr. 2013.
Mcleod, Howard. "Genetic Basis of Drug Metabolism." Medscape. American Society for
Clinical Investigation, 2002. Web. 12 Apr. 2013.
<http://www.medscape.com/viewarticle/444804_5>.
Parker, Nathan. "Articles." Primary Psychiatry: Trichotillomania: Apparent CYP 2D6
Interaction with Amphetamine and Paroxetine. N.p., n.d. Web. 12 Apr. 2013.
<http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=327>.
Rothman, RB. "Result Filters." National Center for Biotechnology Information. U.S.
National Library of Medicine, 11 July 2006. Web. 12 Apr. 2013.
<http://www.ncbi.nlm.nih.gov/pubmed/16835371>.