C H APT E R 44

Psychostimulants and
Wakefulness-Promoting Agents
Charles DeBattista, D.M.H., M.D.

Amphetamine, first discovered in 1887, and the subsequently developed

stimulants have been used in clinical psychiatry with varying results. Beyond
their use for attention-deficit/hyperactivity disorder (ADHD), stimulants have
been used for symptomatic relief based on their effects on mood and hedonic
drive. Research into the use of stimulants as adjunctive agents in the
treatment of specific symptoms and syndromes has been increasing. Various
common adjunctive psychotherapeutic uses for stimulants, such as
depression, have not been well researched, whereas other indications, such
as narcolepsy, are backed by considerable clinical data. In this chapter, I
review the pharmacology of these medications and their indications (Tables
44–1 and 44–2).

T ABLE 44–1. FDA classifications of psychostimulants and wakefulness-

promoting agents

Abuse
Agent Schedule Approved for Medication type potential
Amphetamine II ADHD, Anorexiant/stimulant Black box
narcolepsy warning
Lisdexamfetamine II ADHD Stimulant Black box
warning
Methylphenidate II ADHD, Anorexiant/stimulant Black box
narcolepsy (“Mild stimulant”) warning
Modafinil IV Excessive Wakefulness- Reinforcing
daytime promoting agent
sleepiness
associated
with
narcolepsy,
OSAHS,
and SWSD
Armodafinil IV Excessive Wakefulness- Reinforcing
daytime promoting agent
sleepiness
associated
with
narcolepsy,
OSAHS,
and SWSD
Note. ADHD=attention-deficit/hyperactivity disorder; FDA=U.S. Food and Dru
Administration; OSAHS=obstructive sleep apnea/hypopnea syndrome; SWSD=shif
work sleep disorder.
Source. Adapted from Physicians’ Desk Reference, 60th Edition. Montvale, NJ, Medical Economics Company, 2006.

T ABLE 44–2. Amphetamine and methylphenidate preparations

Time to Peak Duration

Stimulant effect (hours) (hours) Dosing
Amphetamine preparations
Adderalla ~1 hour 3 6–9 bid
Adderall XR 1–2 hours 7 6–10 qd (or
bid)
Dexedrine 1 hour 3 4–6 bid or tid
Dexedrine Spansules 1 hour 4 6–10 qd or bid
Desoxyn 40 minutes 1–3 4–24 qd, bid,
(methamphetamine) or tid
Vyvanse ~1 hour 2 9 qd
Vyvanse ~1 hour 2 9 qd
(lisdexamfetamine)
Methylphenidate preparations
Methylphenidate 15–30 1–2 4–5 bid or tid
minutes
Focalin 15–30 1–2 4–5 bid or tid
(dexmethylphenidate) minutes
Ritalin SR (tablet) 1–2 hours 5 8 qd or bid
Concertab 1–2 hours 6–8 12 qd or bid
Metadate-CDc 1 hour Biphasic: 6–8 qd or bid
1–2 and
4–5
Note. bid = twice daily; qd = once daily; tid = three times daily.
a
Amphetamine/dextroamphetamine, 1:3 ratio.
b
Laser hole in capsule allows passage of drug; osmotically active push layer
expels drug.
c
Rapid-release and continuous-release beads give biphasic response.

Amphetamines

Structure–Activity Relations
Structurally, amphetamine is phenylisopropylamine. Ultimate pharmacological
action is determined by alterations to any of the three basic parts of the
amphetamine molecule.

Amine Changes
In terms of affecting clinical utility, substitution at the amine group is the
most common alteration. Methamphetamine (both L and D isomers), which is
characterized by an additional methyl group attached to the amine, making it
a secondary substituted amine, is more potent than amphetamine. Usefully,
one may think of the amine group as enhancing stimulant-like properties.
Isopropyl Changes
An intact isopropyl side chain appears to be needed in order to maintain the
potency of amphetamine. For example, changing the propyl to an ethyl chain
creates phenylethylamine, an endogenous neuroamine (a metabolite of the
monoamine oxidase inhibitor [MAOI] phenelzine) that has mood- and energy-
enhancing properties but less potency and a much shorter half-life than
amphetamine (Janssen et al. 1999).

Aromatic Changes
Substitutions on the phenyl group are associated with a decrease in
amphetamine-like properties. Interestingly, reduction of the phenyl to a
cyclohexyl ring reduces the potency, but not the efficacy, of amphetamine
properties. Unlike changes at the amine or isopropyl level, additions to the
aromatic ring substantially alter the effects of the compound. The most
common changes at the aromatic ring are of the methoxy type and are
associated with hallucinogenic properties.

Stereospecificity
In recent years there has been renewed interest in drugs that are pure
stereoisomers, as opposed to racemic mixtures, especially with the release of
dexmethylphenidate (the dextro isomer of methylphenidate) and
escitalopram (the levo isomer of citalopram). In amphetamine isomers, it is
true that the dextro form (i.e., dextro isomer, or dextroamphetamine) is
almost twice as potent as the levo form (i.e., levo isomer, or
levoamphetamine) in promoting wakefulness, but they are of equal potency
in reducing cataplexy and rapid eye movement (REM) sleep (Nishino and
Mignot 1997). The effect on dopamine reuptake is stereospecific; inhibition in
rat brain, striatum, and hypothalamus has been found to be markedly
different between the two isomers (Ferris and Tang 1979).
The clinical utility of stereospecificity is unclear. Urine levels of the levo
isomer have been used to measure compliance in amphetamine-addicted
patients prescribed dextroamphetamine for maintenance or detoxification;
the logic is that the more levo isomer present in urine, the less compliance
(George and Braithwaite 2000).
Perhaps the most clinically useful difference between amphetamine
isomers involves their differential effects on reinforcement. Studies in rats
have shown that the dextro isomer is four times more potent than the levo
isomer in promoting lever pressing for intracranial stimulation (Hunt and
Atrens 1992). However, that pure dextroamphetamine is better for the
treatment of ADHD than, for example, the mixed salts of
dextroamphetamine/amphetamine is neither obvious nor conclusively shown.
In addition, the overall greater potency of the dextro form for central actions
suggests that this form may have a higher potential for abuse.

Pharmacological Profile
Amphetamines are noncatecholamine, sympathomimetic amines with central
nervous system (CNS) stimulant activity that causes catecholamine efflux and
inhibits the reuptake of these neurotransmitters (see subsection “Mechanism
of Action” later in this section).

Pharmacokinetics and Disposition

Amphetamine is highly lipid soluble and reaches peak levels in approximately
2 hours. Because of this lipid solubility, amphetamine has rapid distribution
into tissues and transit across the blood–brain barrier. The protein binding is
highly variable, but the average volume of distribution (Vd) is 5 L/kg.
The half-life of amphetamine is approximately 16–30 hours. On average,
30% of amphetamine is excreted unchanged.

Mechanism of Action
The classic mechanism of action of amphetamine involves rapid diffusion
directly into neuron terminals; through dopamine and norepinephrine
transporters, amphetamine enters vesicles, causing release of dopamine and
norepinephrine. The release of these neurotransmitters into the synapse
mediates some of the psychological and motoric effects of amphetamine,
including euphoria, increased energy, and locomotor activation.

Side Effects and Toxicology

Side Effects and Toxicology
The side effects of amphetamines are predictable relative to their
sympathomimetic pharmacology. The most common effects are nervousness,
agitation, and decreased sleep. Serious adverse consequences have been
observed with amphetamines and include arrhythmias, hyperpyrexia,
rhabdomyolysis, and convulsions. Death, although uncommon, generally
occurs only after the manifestation of one of these symptoms. Hallucinosis
and psychosis are frequent complications of injected or inhaled
amphetamines but are uncommon with oral intoxication.
Methamphetamine is more frequently associated with complications;
because of its higher toxicity, it is not clear whether severe complications are
dose dependent. For example, in a retrospective study of methamphetamine-
related deaths in a large city, methamphetamine use was significantly
associated with a higher risk of coronary artery disease, as well as a higher
rate of subarachnoid hemorrhage, although it was of course impossible to
determine whether the subjects were first-time users or chronic abusers
(Karch et al. 1999). Of particular note in this study, however, was that blood
levels of methamphetamine did not differ between the group in which
methamphetamine was judged to be the cause of death and the group in
which methamphetamine was detected but judged not to be related to the
cause of death, suggesting that these toxicities are not necessarily dose
dependent. Similarly, in one 5-year study, methamphetamine accounted for
43% of rhabdomyolysis cases in an emergency department setting.
Methamphetamine is more neurotoxic than amphetamine; it can cause
destruction of dopaminergic neurons in the basal ganglia and thus is widely
thought to increase the likelihood of future parkinsonism (Guilarte 2001).
Although it is commonly believed that MDMA (3,4-methylenedioxy-N-
methamphetamine; “Ecstasy”) is toxic primarily to serotonergic neurons
(Sprague et al. 1998), evidence shows that it is also toxic to dopaminergic
neurons (Ricaurte et al. 2002).
Seizures are fairly common in amphetamine abuse scenarios, especially
with the more potent methamphetamine and hallucinogenic analogs.
Stimulant psychosis—often referred to as paranoid psychosis—is also
common in amphetamine abuse scenarios because of the overwhelming
presentation of the eponymous symptom. Visual hallucinations are also
disproportionately common with amphetamine psychosis. Psychosis is often
seen together with stereotypy. In humans, stereotypy can take many forms
but usually is expressed as pacing, searching, or examining minute details.

Drug–Drug Interactions
A comprehensive review found that drug interactions with amphetamine were
mostly pharmacodynamic in nature (Markowitz and Patrick 2001); however,
because a small portion of amphetamine metabolism occurs via the
cytochrome P450 (CYP) 2D6 isoenzyme, those drugs that inhibit 2D6
metabolism can, theoretically, have the effect of increasing the plasma level
of amphetamine.

Lisdexamfetamine
Lisdexamfetamine dimesylate, a prodrug that on absorption is metabolized to
dextroamphetamine and L-lysine, was approved in 2007 for the treatment of
ADHD. Food does not affect absorption of lisdexamfetamine, but acidification
of the urine results in more rapid clearance.
Two small studies in children found good efficacy and tolerability for
lisdexamfetamine in the treatment of ADHD. A 4-week randomized, double-
blind, forced-dose, parallel-group study compared lisdexamfetamine 30, 50,
or 70 mg/day with placebo in children (ages 6–12 years) with ADHD
(Biederman et al. 2007b). Efficacy, as measured by scores on the ADHD
Rating Scale—Version IV (ADHD-RS-IV), the Conners Parent Rating Scale
(CPR), and the Clinical Global Impression–Improvement (CGI-I) scale, was
statistically superior to that of placebo for all dosages tested. A randomized,
double-blind, placebo-controlled crossover study compared lisdexamfetamine
with placebo and extended-release mixed amphetamine salts (Adderall XR) in
52 children (ages 6–12 years) with ADHD in an analog classroom setting
(Biederman et al. 2007a). The study found comparable efficacy and safety for
the active medications and superiority over placebo as measured by scores
on the CGI-I scale and the Swanson, Kotkin, Agler, M-Flynn, and Pelham