Objectives: -To educate prescribers about controlled substance scheduling. -To educate prescribers about the pharmacology of amphetamines -To educate prescribers about the indications for the proper use of psychostimulants -To educate prescribers about discontinuation and tapering strategies

1. Amphetamines
Presented by Alexis Polles, MD
For the MS Medical Assocciation
May 23-28, 2013
Sandestin

2. Disclosures
 None to disclose
 Non-approved use of amphetamine for
“performance enhancement” and others will
be mentioned. These are not currently FDA
recommended uses of these substances.

3. Outline
 Amphetamine – structure, function, mechanism of
action, effects, uses, contraindications
 Amphetamine – abuse
 Specific Disease Applications
 Narcolepsy
 ADD/ADHD
Note: Many slides contain information for your review and
may not be discussed in detail in order to conserve time.
You may contact me for any questions at
agpolles@comcast.net or 601-520-4814.

4. Amphetamines: recommendations for
appropriate use
Objectives:
1.To educate prescribers about controlled substance scheduling.
2.To educate prescribers about the pharmacology of amphetamines
3.To educate prescribers about the indications for the proper use of
psychostimulants
4.To educate prescribers about discontinuation and tapering
strategies

5. Description
 Amphetamine is a stimulant that is now primarily used to treat narcolepsy
and attention-deficit hyperactivity disorder. It is also used recreationally as a
club drug and as a performance enhancer.
 The name amphetamine is derived from its chemical name alpha-
methylphenethylamine.
 Initially, amphetamine was more popularly used to diminish the appetite and
to control weight.
 Because of the widespread use of amphetamines as a treatment for
narcolepsy and ADD/ADHD, prescription amphetamines are subject to
diversion and are one of the most frequently- abused drugs in high schools
and colleges.
HO
HO
NH2
OH
Norepinephrine
(Noradrenaline)
NH2
Amphetamine
CH3
NHCH3
Methamphetamine
CH3
Methylphenidate
(RitalinTM)
H
N
O O
Me

6. Brand Names
 Brand names of the medications that contain,
or metabolize into, amphetamine include
"Adderall", "Dexedrine", "Dextrostat",
"Desoxyn", "ProCentra", "Vyvanse", and
"Benzedrine" in the past.

7. Adderall(dextroamphetamine/amphetamine)-High Abuse Potential, Dependency
Avoid prolonged tx, may lead to drug dependence; potential for non-therapeutic use or
distribution to others; prescribe/dispense sparingly; serious cardiovascular adverse events and
sudden death reported w/ misuse
 Adult Dosing: Dosage forms: 5,7.5,10,12.5,15,20,30
 ADHD
 [5-40 mg/day PO div qd-tid] Start: 5 mg PO qam or bid, incr. 5 mg/day qwk; Info: give divided doses at 4-6h intervals; doses >40 mg/day
rarely more effective
 narcolepsy
 [5-60 mg/day PO div qd-tid] Start: 10 mg PO qam, incr. 10 mg/day qwk; Info: give divided doses at 4-6h intervals
 renal dosing [not defined] hepatic dosing [not defined]
 Peds Dosing : Dosage forms: 5,7.5,10,12.5,15,20,30
 ADHD
 [3-5 yo] Dose: 2.5-40 mg/day PO div qd-tid; Start: 2.5 mg PO qam, incr. 2.5 mg/day qwk; Info: give divided doses at 4-6h intervals; doses
>40 mg/day rarely more effective [>6 yo] Dose: 5-40 mg/day PO div qd-tid; Start: 5 mg PO qam or bid, incr. 5 mg/day qwk; Info: give
divided doses at 4-6h intervals; doses >40 mg/day rarely more effective
 narcolepsy
 [6-12 yo] Dose: 5-60 mg/day PO div qd-tid; Start: 5 mg PO qam, incr. 5 mg/day qwk; Info: give divided doses at 4-6h intervals [>12 yo]
Dose: 5-60 mg/day PO div qd-tid; Start: 10 mg PO qam, incr. 10 mg/day qwk; Info: give divided doses at 4-6h intervals
 Metabolism: liver; CYP450: 2D6 substrate; Info: active metabolites
 Excretion: urine; Half-life 9-14h; Info: pH-dependent excretion
 XR: Peds Dosing .
 Dosage forms: 5,10,15,20,25,30 ER ADHD
 [6-12 yo] Dose: 10 mg PO qam; Start: 5-10 mg PO qam, incr. 5-10 mg/day qwk; Max: 30 mg/day; Info: may convert from IR to ER at
same total daily dose qam [13-17 yo] Dose: 10-20 mg PO qam; Start: 10 mg PO qam, incr. 10 mg/day qwk; Max: 40 mg/day; Info: may
convert from IR to ER at same total daily dose qam; doses >20 mg/day rarely more effective
 renal dosing [not defined]
 hepatic dosing [not defined]
 Metabolism: liver; CYP450: 2D6 substrate; Info: active metabolites
 Excretion: urine; Half-life 9-14h; Info: pH-dependent excretion

8. Vyvanse(lisdexamfetamine)-Epocrates Online
Adult Dosing .
 Dosage forms: 20,30,40,50,60,70
 ADHD
 [30 mg PO qam] Max: 70 mg/day; Info: may incr. dose 10-20 mg/day qwk; use lowest effective
dose
 renal dosing [not defined] hepatic dosing [not defined]
Peds Dosing .
 Dosage forms: 20,30,40,50,60,70
 ADHD
 [6-17 yo] Dose: 30 mg PO qam; Max: 70 mg/day; Info: may incr. dose 10-20 mg/day qwk; use
lowest effective dose
 renal dosing[not defined] hepatic dosing [not defined]
 Metabolism: liver; CYP450: 2D6 (weak) inhibitor; Info: prodrug converted to dextroamphetamine
 Excretion: urine 96%, feces 0.3%; Half-life: <1h, 12h (dextroamphetamine); Info: pH-dependent
excretion
High Abuse Potential, Dependency: high abuse potential; avoid prolonged tx, may lead to
drug dependence; potential for non-therapeutic use or distribution to others;
prescribe/dispense sparingly; serious cardiovascular adverse events and sudden death
reported w/ misuse

9. From Medline Release
 November 16, 2010 — The US Food and Drug
Administration (FDA) has approved
lisdexamfetamine dimesylate capsules (Vyvanse;
Shire Pharmaceuticals, Inc) for the treatment of
attention deficit hyperactivity disorder (ADHD) in
adolescents aged 13 to 17 years.
 FDA approval was based on data from a double-
blind, 4-week (emphasis mine), randomized,
forced-dose escalation study of 314 adolescents
showing that lisdexamfetamine doses of 30, 50, and
70 mg/day significantly improved ADHD symptoms
relative to placebo, as evaluated using the ADHD
Rating Scale-IV.

10. DEA Schedule
 In the United States, amphetamine and
methamphetamine are Schedule II drugs,
classified as CNS (central nervous system)
stimulants.
 A Schedule II drug is classified as one that
has a high potential for abuse, has a
currently-accepted medical use and is used
under severe restrictions, and has a high
possibility of severe psychological and
physiological dependence.

11. Historical
 Amphetamine was synthesized in 1887 by Lazar Edeleanu at the
University of Berlin. It was one of a series of compounds related to
the plant derivative Ephedrine, which had been purified two years
previously.
 No medical use was found for Amphetamine until the 1900s, when it
was introduced in most of the world in the form of the pharmaceutical
Benzedrine. This drug was used by the militaries of several nations,
especially the air forces, to fight fatigue and increase alertness
among servicemen.
 After decades of reports of abuse, the FDA banned Benzedrine
inhalers, and limited amphetamines to prescription use in 1959, but
illegal use became common.

12. Historical
 The related compound methamphetamine was
first synthesized from ephedrine in Japan in 1893
by chemist Nagayoshi Nagai.
 In 1919, crystallized methamphetamine was
synthesized by Akira Ogata via reduction of
ephedrine using red phosphorus and iodine.
 The German military was notorious for their use
of methamphetamine in World War II.

13. Endogenous amphetamines
 Amphetamine has been found to have several
endogenous analogues; that is, molecules of a
similar structure found naturally in the brain.
 l-Phenylalanine and β-Phenethylamine are two
examples, which are formed in the peripheral
nervous system as well as in the brain itself.
 These molecules are thought to modulate levels of
excitement and alertness, among other related
affective states.

14. Hypotheses of How Amphetamine Affects
Dopamine
 The most widely studied neurotransmitter with regard to
amphetamine action is dopamine (DA).
 DA is highly active in numerous reward pathways of the brain.
 Amphetamine increases the concentrations of dopamine in the
synaptic cleft.
 The specific mechanisms by which amphetamine affects
dopamine concentrations have been studied extensively.
 One theory emphasizes amphetamine’s actions on the vesicular
level: Amphetamine increases concentrations of dopamine in the
cytosol of the pre-synaptic neuron.
 The other focuses on the role of the dopamine transporter DAT:
Amphetamine may interact with DAT to induce reverse transport
of dopamine from the presynaptic neuron into the synaptic cleft.

15. Storage
Synthesis
Precursor
Release
Reuptake
Degradation
Synaptic
Cleft
= vesicle
= neurotransmitters
= receptor

16. Hypotheses of How Amphetamine Affects
Serotonin and Glutamate
 Amphetamine has been found to exert similar effects on
serotonin as on dopamine in particular regions of the
brain, such as the mesocorticolimbic projection.
 Recent studies additionally postulate that amphetamine
may indirectly alter the behavior of glutamatergic
pathways. Increased extracellular concentrations of
serotonin may thus modulate the excitatory activity of
glutamatergic neurons.

17. Dopamine
Neurotransmission
VTA/SN
nucleus
accumbens
frontal
cortex
0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
AMPHETAMINE
0
50
100
150
200
0 60 120 180
Time (min)
%ofBasalRelease Empty
Box Feeding
Di Chiara et al.
FOOD

18. 0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens AMPHETAMINE
0
100
200
300
400
0 1 2 3 4 5 hr
Time After Cocaine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens
COCAINE
0
100
150
200
250
0 1 2 3 4 5hr
Time After Morphine
%ofBasalRelease
Accumbens
0.5
1.0
2.5
10
Dose (mg/kg)
MORPHINE
0
100
150
200
250
0 1 2 3 hr
Time After Nicotine
%ofBasalRelease
Accumbens
Caudate
NICOTINE
Di Chiara and Imperato, PNAS, 1988
Effects of Drugs on Dopamine Release

19. Amphetamine Tolerance
 Tolerance is developed rapidly in amphetamine abuse, therefore
increasing the amount of the drug that is needed.
 Short term tolerance can be caused by depleted levels of
neurotransmitters within the vesicles available for release into the
synaptic cleft following subsequent reuse (tachyphylaxis).
 Short term tolerance typically lasts 2-3 days, until neurotransmitter
levels are fully replenished.
 Prolonged overstimulation of dopamine may eventually cause the
receptors to downregulate in order to compensate for increased
levels of dopamine within the synaptic cleft.

20. Effects
Central:
Short term use: euphoria, anxiety, increased libido, alertness,
concentration, energy, self-esteem, self-confidence, sociability,
grandiosity, excessive feelings of power and invincibility (mimics
mania), repetitive and obsessive behaviors, paranoia, and with high
doses, amphetamine psychosis can occur.
Other central effects include insomnia, irritability, weakness,
tremor, confusion, delirium, panic states and suicidal
tendencies.
Chronic use: Can produce psychosis, mood changes,chronic
irritability.
The anorectic effect of amphetamine is due to direct action in the
feeding center located In the lateral hypothalamus.

21. Effects
Peripheral:
Cardiovascular effects: palpitations, tachyarrthymias, hypertension
acute coronary ischemia and cardiovascular collapse can occur.
GI effects: Nausea, vomiting, abdominal cramps and diarrhea.

22. Contraindications
 Amphetamine elevates cardiac output and blood pressure
making it dangerous for use by patients with a history of heart
disease or hypertension.
 Amphetamine can cause a life-threatening complication in
patients taking MAOI antidepressants.
 The use of amphetamine and amphetamine-like drugs is
contraindicated in patients with narrow-angle glaucoma or
anatomically narrow angles. Like other sympathomimetic
amines, amphetamine can induce transient mydriasis.
 These agents should also be avoided in patients with other forms
of glaucoma, as mydriasis may occasionally increase intraocular
pressure.
 Amphetamine has been shown to pass through into breast milk.
Because of this, mothers taking amphetamine are advised to
avoid breastfeeding during their course of treatment.

23. Withdrawal effects
 Withdrawal symptoms of amphetamine primarily
consist of mental fatigue, mental depression and an
increased appetite.
 Symptoms may last for days with occasional use
and weeks or months with chronic use, with severity
dependent on the length of time and the amount of
amphetamine used.
 Withdrawal symptoms may also include anxiety,
agitation, excessive sleep, vivid or lucid dreams,
deep REM sleep and suicidal ideation.

24. Detection in body fluids
 Amphetamine is frequently measured in urine as part of drug
abuse programs, etc.
 Techniques such as immunoassay may cross-react with a
number of sympathomimetics drugs, so chromatographic
methods specific for amphetamine should be employed to
prevent false positive results.

25. Yep, alkalinizing your system does increase
amphetamine absorption/decrease degradation. In
addition to sodium bicarbonate you can use Tums
(calcium carbonate) as well -- the combo works
nicely, and has the added benefit of settling the
stomach.
Unfortunately, you should have SOME antioxidants
around (to reduce neurotoxicity), and alpha lipoic
acid (as well as vitamin c --both are acidic,
obviously), is the best antioxidant. I try and take it a
few hours before doing any stimulants, as well as
several hours into the stimulant use. You can also
take non-acidic antioxidants like vitamin E and
selenium.
Excretion of amphetamine is pH dependent

26. Food for thought: “First Do No Harm.”
Science has generated much
evidence showing that…
prolonged drug use
changes
the brain in fundamental
and long-lasting ways

27. Specific Disease Application:
Narcolepsy

28. Diagnostic criteria for Narcolepsy
 A. Irresistible attacks of non-refreshing sleep that occur daily over at
least 3 months.
 B. The presence of one or both of the following:
 (1) cataplexy (i.e., brief episodes of sudden bilateral loss of muscle
tone, most often in association with intense emotion)

(2) recurrent intrusions of elements of rapid eye movement (REM) sleep
into the transition between sleep and wakefulness, as manifested by
either hypnopompic or hypnagogic hallucinations or sleep paralysis at
the beginning or end of sleep episodes
 C. The disturbance is not due to the direct physiological effects of a
substance (e.g., a drug of abuse, a medication) or another general
medical condition.
Hypnopompic hallucination: A vivid dreamlike hallucination that occurs as one is waking up. The opposite of an hypnagogic
hallucination, which occurs as one is falling asleep.

29. Specific Disease Application:
ADHD

30. ADHD Tidbits
 Its symptoms can be difficult to differentiate from other disorders.
 ADHD and its diagnosis and treatment have been considered controversial since
the 1970s.The controversies have involved clinicians, teachers, policymakers,
parents and the media. Topics include the actuality of the disorder, its causes,
and the use of stimulant medications in its treatment.
 Most healthcare providers accept that ADHD is a genuine disorder with
debate in the scientific community centering mainly around how it is
diagnosed and treated.

31. American Academy of Pediatrics
Guidelines for Treating ADHD
 Set specific, appropriate target goals to guide therapy.
 Start medication and non-pharmacologic therapy.
 When treatment has not met the target goals, re-evaluate the original
diagnosis, the possible presence of other conditions, and how well the
treatment plan has been implemented.
 Follow-up regularly with the doctor to check on goals, results, and any
side effects of medications. During these check-ups, information should
be gathered from parents, teachers, and the child.

32. ADHD or Stimulant Seeking?
 Prevalence of ADHD worldwide is 5.2%
 Prevalence in the US is 9.5%
Riddle MA, et al. J Am Acad Child Adoles
Psychiatry. 2013; 52:264-278

33. How Do Know It’s ADHD?
 AACAP guidelines for ADHD diagnosis
 Symptoms at home, school, other settings
 Report of patient, parent, teachers, coaches
 History since childhood (before age 12)
 Rule out other disorders
 Use validated diagnostic tools
 Give the diagnosis the time it deserves

34. ADHD vs. SUD Diagnosis
 Do symptoms co-occur with substance use?
 If yes, then additional symptoms may be a
consequence of substance use rather than ADHD
 Did ADHD symptoms begin before or after
regular substance abuse?
 Is there a temporal relationship of symptoms
with other comorbidities?

35. The Dilemma: Are we preventing drug addiction in kids with ADHD or
are we contributing to it? About half the large studies to date
indicate that early recognition and treatment reduces later rates of
addiction. However…….
 In a 13 year prospective study which looked at adult
cocaine users, it was found that those individuals who used
Ritalin for ADHD between one and ten years of age had a
percentage of cocaine abuse twice that of those who had
been diagnosed with ADHD but had not utilized Ritalin.
Though use of Ritalin may not explain all reasons someone
may begin to utilize drugs, there is a correlation between
length of use of Ritalin and later drug use.
Russell A. Barkley, PhD,et al. (2003). "Does the Treatment of Attention-
Deficit/Hyperactivity Disorder With Stimulants Contribute to Drug Use/Abuse? A 13-Year
Prospective Study". PEDIATRICS. 2003 Vol. 111 No. 1: pp. 97-109

36. Early ADHD Treatment Linked to Lower Risk for
Substance Use Disorders until age 18
Information sourced from NEJM Journal Watch
 Researchers conducted an industry-supported, prospective,
longitudinal study. Participants were followed for a mean of 4 years
until a mean age of 16. There were three groups: 327 ADHD patients treated with stimulants (85%
male), 61 untreated ADHD patients (59% male), and 211 healthy controls (41% male).
 Untreated patients had a significantly higher risk for SUDs than
treated patients (hazard ratio, 1.91). Younger age at beginning
stimulants was associated with lower risk for SUDs — until age 18,
after which SUD risk increased. Controlling for oppositional defiant
disorder, conduct disorder, and sex did not affect the results.
 A study limitation is that by the end of the study, participants were
typically still younger than the mean age (20 years) for onset of
SUDs (Arch Gen Psychiatry 2005; 62:593). Barbara Geller, MD
reviewing Groenman AP et al. Br J Psychiatry 2013 Jul 11.

38. ADHD Treatments Not Working for
Most Young Children
SOURCE: Johns Hopkins Medicine, news release, Feb. 11,
2013
N=186, 3-5 year olds
For six years, researchers tracked the severity
of the three primary ADHD symptoms:
inattention, hyperactivity and impulsivity.
2/3 were on stimulant medications
90% continued to have symptoms

39.  62% of kids on meds. Vs 58% with no meds.
had “significant hyperactivity and impulsivity”
 65% on meds. Vs 62% no meds. had
“serious inattention”
 The study was funded by the U.S. National Institute of
Mental Health and published online Feb. 11 in the
Journal of the American Academy of Child & Adolescent
Psychiatry.

40. Adult ADHD:
About 4 percent of adults (General Population) have attention deficit
hyperactivity disorder (ADHD). (About half of kids with ADHD still have it in
adulthood.) If you are an addict, the percentages go way up.
Though you may have strong urges to help the person somehow, please do
not prescribe stimulants to alcoholics or addicts thinking it will
improve their chances for cessation of substance abuse.
A diagnosis can be important. Adults with ADHD tend to have lower
incomes as well as higher rates of accidents, unplanned pregnancies, and
substance abuse than those without it.

41. The Challenges
 ADD is very difficult to diagnose
 There is no distinct profile on testing, most of what is used in adults is self-report,
and even sophisticated testing can be “fooled”
 Expectancy effects on self-report of symptoms and treatment (with stimulants) are
large
 Because a person likes having more energy and can “get more done” on
stimulants, it does not mean they have ADD.
 Most experienced practitioners, if they are brutally honest with themselves, will
probably admit that they are not completely sure about the diagnosis in adults.
 The best predictor of the likely diagnosis of ADD is the patient deciding they have it.
 ADD symptoms and personality traits are difficult to differentiate.
 People want a quick fix.

42. Non-Disease Unapproved Use
“Performance Enhancement”

43. Performance-enhancing use
 Amphetamine is used by some college (est. 25% +) and high-school
students as a study and test-taking aid. Adults use it to improve their ability
to work when fatigued, and some give them to their children to give the
children a supposed edge.
 Amphetamine has been, and is still, used by militaries around the world.
 Amphetamine is also used by some professional, collegiate, and high school
athletes for its strong stimulant effect.
 Amphetamine use has historically been especially common among Major
League Baseball players; the league banned the use of amphetamine in
2006. The ban is enforced through periodic drug-testing.
 Amphetamine was formerly in widespread use by truck drivers to combat
symptoms of somnolence and to increase their concentration during driving,
especially in the decades prior to the signing by former president Ronald
Reagan of Executive Order 12564, which initiated mandatory random drug
testing of all truck drivers and employees of other DOT-regulated industries.

46. Don't Give ADHD Meds to Undiagnosed Kids, Experts Urge
Neurologists say some doctors are prescribing these drugs as a way to boost
school performance
By Barbara Bronson Gray
HealthDay Reporter
WEDNESDAY, March 13 (HealthDay News) -- Some people call it "brain doping" or "meducation."
Others label the problem "neuroenhancement." Whatever the term, the American Academy of
Neurology has published a position paper criticizing the practice of prescribing "study drugs" to boost
memory and thinking abilities in healthy children and teens.