H.
Substances of Abuse
73 AMPHETAMINES
Meghan B. Spyres and David H. Jang
NH
O CH3
H2C
CH3
O 2,5-methoxyphenylethylamine (2CB) were popular in dance clubs in the
Methylenedioxymethamphetamine
OH
NH HO NH
CH3 CH3
CH3
HO
Methamphetamine Epinephrine
HISTORY AND EPIDEMIOLOGY
Amphetamine was first synthesized in 1887 but was essentially lost until
the 1920s, when concerns arose regarding the supply of ephedrine for
asthma therapy.67 The attempt to synthesize ephedrine lead to the redis-
covery of dextroamphetamine in the United States and methamphetamine
(d-phenylisopropylmethylamine hydrochloride) in Japan. Amphetamine was
first marketed by Smith, Kline, and French in 1932 as the nasal decongestant
Benzedrine. Both amphetamine and methamphetamine were supplied as
stimulants for soldiers and prisoners of war during World War II. Amphet-
amine tablets were later available in 1935 for the treatment of narcolepsy and
were advocated as anorexiants in 1938.17
The stimulant and euphoric effects of amphetamine were immediately
recognized, with abuse reported as early as 1940.74 As a result, Benzedrine
inhalers were banned by the US Food and Drug Administration (FDA) in
1959. From 1950 to the 1970s, there were sporadic periods of widespread
amphetamine use and abuse in the United States. In the 1960s and early
1970s, various amphetamines such as methylenedioxyamphetamine (MDA),
para-methoxyamphetamine (PMA), and para-methoxymethamphetamine
(PMMA) were popularized as hallucinogens.97,127 The Controlled Substance
Act of 1970 placed amphetamines in Schedule II to prevent the diversion of
pharmaceutical amphetamines for nonmedicinal uses. Abuse of amphet-
amines subsequently declined.136
In the 1980s, use of methylenedioxy derivatives of amphetamine and
methamphetamine surfaced and circumvented existing regulations.
The best known of these derivatives were 3,4-methylenedioxymetham-
phetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).6
Since the late 1980s, a dramatic resurgence of methamphetamine abuse
has spread throughout much of the United States. A high-purity prepara-
tion of methamphetamine hydrochloride was illegally marketed in a large
crystalline form termed “ice” by abusers.46 Methamphetamine-related
deaths in the United States increased through the 1990s, initially at sev-
eral hundred per year. From 2010 to 2014, deaths involving methamphet-
amine doubled from 1,388 to 3,728 per year.171 Men who have sex with men
in New York City (and perhaps elsewhere) remain a specific population at
risk, with a persistently high prevalence of methamphetamine use.72 The
ease and low cost of methamphetamine synthesis encourage establish-
ment of illegal clandestine laboratories in the United States.72 Since the
mid-1990s, MDMA has been widely used by college students and teenagers
in large gatherings, known as “rave” or “techno” parties, in Europe and the
United States.134 Methcathinone (a khat-derived substance) and 4-bromo-
Midwestern United States in the 1990s, but use was not widespread.59,62
Synthetic cathinones are currently sold as “bath salts” or “legal highs”
to circumvent existing laws, resulting in serious toxicity and deaths.31
Recently, older amphetamines such as PMA and PMMA made a resur-
gence, with new reports of toxicity and deaths.102
PHARMACOLOGY
Amphetamine is the acronym for racemic β-phenylisopropylamine. Amphet-
amine is representative of a broader group of compounds with a shared
phenylethylamine structure, which is a more accurate term. Numerous
substitutions on the phenylethylamine backbone are possible, resulting
in a variety of xenobiotics, some with unique properties. For the purposes
of this chapter, all phenylethylamines, even those that are not actually
amphetamines, will be called amphetamines for simplicity, and the name
amphetamine specifically refers to β-phenylisopropylamine.
The pharmacologic effects of amphetamines are complex, but their
primary mechanism of action is the release of biogenic amines. Release of
catecholamines from the presynaptic terminals, particularly dopamine and
norepinephrine, leads to a hyperadrenergic condition, but release of sero-
tonin favors a serotonergic condition. Although there are conflicting mech-
anistic models of amphetamine induction of catecholamine release, these
variable results are directly correlated with the different concentrations
of amphetamine used in experimental models. Our understanding of the
mechanism of action of amphetamines is based on dopaminergic neurons;
similar mechanisms occur with norepinephrine and serotonin. Two storage
pools exist for dopamine in the presynaptic terminals: the vesicular pool and
the cytoplasmic pool. The vesicular storage of dopamine and other biogenic
amines is maintained by the acidic environment within the vesicles and the
persistence of a stabilizing electrical gradient within the cytoplasm. This
environment is maintained by an adenosine triphosphate–dependent active
proton transport system.115,145
Amphetamines enter the nerve cell either by passive diffusion or by
exchange diffusion through a reuptake transporter that is partially dose
dependent. At low concentrations, amphetamines enter the cell by
exchange diffusion at the dopamine reuptake transporter and cause the
release of dopamine from the cytoplasmic pool. At moderate concentrations,
amphetamines passively diffuse through the presynaptic terminal mem-
brane and interact with the neurotransmitter transporter on the vesicular
membrane to cause exchange release of dopamine into the cytoplasm. Dopa-
mine is subsequently released into the synapse by reverse transport at the
dopamine reuptake site.145,170 At high concentrations, an additional mecha-
nism is invoked as amphetamines diffuse through the cellular and vesicular
membranes. Because amphetamines are bases, they alkalinize the vesicles,
reducing the pH gradient necessary for vesicle integrity, resulting in dopa-
mine release from the vesicles and delivery into the synapse by reverse trans-
port (Chap. 13 and Fig. 73–1).161,162 Amphetamines also block the reuptake of
biogenic amines by competitive inhibition.68,181 However, the contribution of
this to the ultimate clinical effects are likely minor. Amphetamine’s structural
1099
1100 PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Presynaptic cell
Tyrosine
Tyrosine
hydroxylase

Dopa

AADC

DA
DOPGAL
MAO
NE 6

3 NE

Dopamine NET
Norepinephrine 4
Amphetamine
Na+ NE
1 2

G G
1

CNS: excitation
PNS:
CNS: inhibition bronchodilation,
PNS: vasoconstriction increased pulse
vasodilation

Postsynaptic neuron or end organ

FIGURE 73 1. Noradrenergic nerve ending. The postsynaptic membrane represents an end organ or another neuron in the central nervous system
(CNS). The primary mechanism of action of amphetamine is the release of catecholamines, particularly dopamine (DA) and norepinephrine (NE), from the
presynaptic terminals. Two storage pools exist for DA in the presynaptic terminals: the vesicular pool and the cytoplasmic pool. The vesicular storage of DA
and other biogenic amines is maintained by the acidic environment within the vesicles and the persistence of a stabilizing electrical gradient with respect
to the cytoplasm. (1, 2) Activating or antagonizing postsynaptic α- and β-adrenoceptors. (3) Amphetamines release DA or NE from the cytoplasmic pool by
exchange di usion at the DA uptake transporter site in the membrane. (4) Amphetamines di use through the presynaptic terminal membrane and interact
with the neurotransmitter transporter on the vesicular membrane to cause exchange release of DA or NE into the cytoplasm. DA is subsequently released
into the synapse by reverse transport at the DA uptake site. (5) Amphetamine di uses through the cellular and vesicular membranes, alkalinizing the
vesicles, and permitting dopamine release from the vesicles and delivery into the synapse by reverse transport. (6) Inhibiting monoamine oxidase (MAO)
to prevent NE degradation; or inhibiting catechol-O-methyltransferase (COMT) to prevent NE degradation. AADC = aromatic L-amino acid decarboxylase;
DOPGAL = 3,4-dihydroxyphenylglycoaldehyde; G = G protein; NET = membrane norepinephrine uptake transporter; NME = normetanephrine;
PNS = peripheral nervous system.

similarity to amphetamine derived monoamine oxidase inhibitors (MAOIs)
such as tranylcypromine explains their weak MAOI effect, the clinical signifi-
cance of which is unclear.131
Binding selectivity to the neurotransmitter transporters largely deter-
mines the range of pharmacologic effects for a particular amphetamine. The
affinity of MDMA for serotonin transporters, for example, is 10 times greater
than that for dopamine and norepinephrine transporters. With this high
affinity for serotonin transporters, MDMA produces primarily serotonergic
effects.64 Other predominantly serotonergic amphetamines include para-
methoxyamphetamine and bromo-dragonFLY (Table 73–1).
The most identifiable effects of amphetamines are those caused by
excessive biogenic amine release and the resultant stimulation of various
receptors including α-adrenergic, β-adrenergic, dopamine, and serotonin
receptors. The majority of serotonergic neurons in the central nervous
system (CNS) are located in the raphe nuclei, which connects the brain-
stem to the rest of the CNS via serotonergic projections. Within the CNS,
serotonin regulates a wide variety of functions, including, but not limited
to, mood, memory, temperature regulation, sleep, and pain.67 Serotonin is
also involved in the release of antidiuretic hormone, the excessive release of
which leads to hyponatremia. This is particularly associated with amphet-
amines with potent serotonergic effects such as MDMA.73 Additional
effects of serotonin include regulation of fluid secretion and peristalsis, as
well as regulation of many vascular beds, predominantly via vasoconstric-
tion. Peripherally, serotonergic actions of amphetamines can result in car-
cinoidlike effects.103,144
Norepinephrine is another important neurotransmitter central to
the action of amphetamines. Norepinephrine is found in the CNS and is
also released peripherally from postganglionic sympathetic fibers. The
main noradrenergic nucleus in the CNS is the locus ceruleus. Amphet-
amine induced excessive release of norepinephrine within the CNS results
in decreased fatigue and increased attentiveness. Peripherally, norepi-
nephrine acts on the adrenergic receptors (α and β), which mediate
 CHAPTER 73 AMPHETAMINES 1101

TABLE 73 1
Xenobiotic Clinical Manifestations Structure

4-Bromo-2,5-dimethoxyamphetamine (DOB) Marked psychoactive effect, potency > mescaline OCH3

Fantasy, mood altering NH2
Agitation, sympathetic excess
Sold as impregnated paper, like LSD CH3
Br
OCH3

4-Bromo-2,5-methoxyphenylethylamine (2CB, MFT) Relaxation OCH3

Sensory distortion NH2
Agitation
Hallucination
Br
Potency > mescaline
OCH3

Methcathinone (cat, Jeff, khat, ephedrone) Hallucinations O

Sympathetic excess NH
CH3
CH3

4-Methyl-2,5-dimethoxyamphetamine (DOM/STP) (serenity, tranquility, peace) Narrow therapeutic index OCH3

Euphoria, perceptual distortion NH2
Hallucinations, sympathetic excess
CH3
H3 C
OCH3

3,4-Methylenedioxyamphetamine (MDA, love drug) Empathy, euphoria O NH2

Agitation, delirium, hallucinations, death H2 C
O CH3
associated with sympathetic excess
3,4-Methylenedioxyethamphetamine (MDEA, Eve) Comparable to MDMA O NH
CH2
Sympathetic excess H2 C
O CH3 CH3

3,4-Methylenedioxymethamphetamine (MDMA, Adam, molly, ecstasy, XTC) Psychotherapy “facilitator” O NH

CH3
Euphoria, empathy nausea, H2 C
CH3
anorexia, anxiety, insomnia O
Sympathetic excess
para-Methoxyamphetamine (PMA) Potent hallucinogen NH2
Sympathetic excess
CH3
H3CO

2,4,5-Trimethoxyamphetamine Similar to mescaline H3CO NH2

CH3
H3CO
OCH3

LSD = lysergic acid diethylamide.

vasoconstriction and increased cardiac activity, resulting in hypertension
and tachycardia.
The increase in CNS dopamine, particularly in the neostriatum, medi-
ates stereotypical behavior and other locomotor activities as well as reward
pathways.36 The activity of dopamine in the neostriatum appears to be
linked to glutamate release and inhibition of γ-aminobutyric acid (GABA)
efferent neurons.86 Stimulation of the glutamatergic system contributes
significantly to the stereotypical behavior, locomotor activity, and neuro-
toxicity of amphetamines.86,152,153 The effects of serotonin and dopamine
on the mesolimbic system alter perception, cause psychotic behavior and
anorexia.76,160
Structure Modification
Phenylethylamines are chemical structures with an ethyl group backbone
that has an aromatic group and a terminal amine. Specific substitutions
made to the phenylethylamine backbone have led to the wide variety of novel
drugs, described later. Substitutions at different positions of the phenyl-
ethylamine molecule alter the general pharmacology and clinical effects of
1102 PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
amphetamines, as demonstrated by both animal and human observations.
Large-group substitution at the α carbon reduces the stimulant and cardio-
vascular effects of the amphetamine but allows retention of the anorectic
properties (such as phentermine). Substitution at the para position of the
phenyl ring enhances the hallucinogenic or serotonergic effects of amphet-
amines (such as in para-chloroamphetamine and MDMA).60 Although these
generalizations enable an understanding of the effects of amphetamines,
there are many exceptions, and such generalizations do not necessarily
apply after exposure to large doses of a particular molecule. There is a broad
spectrum of clinical effects that derive from the various amphetamines:
methamphetamine results in the most potent cardiovascular effects, and
2,5-dimethoxy-4-bromoamphetamine (DOB) results in the most consequen-
tial hallucinogenic and serotonergic effects.60,117 Table 73–2 further describes
the pharmacology of specific substitutions.
Other specific substitutions are worth noting. The addition of an extra
methyl group to the terminal amine in amphetamine produces metham-
phetamine, greatly increasing CNS activity. This extra methyl group also
makes methamphetamine more lipid soluble, allowing faster penetration
across the blood–brain barrier and more resistance to degradation by
monoamine oxidase. The addition of an α-methyl group results in strong
stimulant, cardiovascular, and anorectic properties.60,117 This is largely
due to resistance to metabolism by monoamine oxidase conferred by the
addition of this group. These characteristics permit better oral bioavail-
ability and longer duration of effect. The α-methyl group in the amphet-
amine structure also introduces chirality to the molecule. With few notable
exceptions including MDMA, the d-enantiomer is typically 4 to 10 times
more potent than the l form of amphetamine. Addition of a methoxy group
to either the 2 or 5 position of the aromatic ring on the amphetamine or
methamphetamine compound increases serotonergic activity. Another
important substitution to the phenylethylamine backbone is the addition
of a halogen group (eg, iodine or bromine), which increases the potency and
neurotoxicity of the compound compared to nonhalogenated compounds.
Neurotoxicity is thought to be due to significant serotonin depletion, lead-
ing to irreversible neuron damage.76 The ability of amphetamines to directly
interact with neurotransmitter transporters enable minor modifications
of the molecule to significantly alter its pharmacologic profile.80 The addi-
tion of a ketone group at the β position results in a group of compounds
TABLE 73 2
3 NH2
4
Substitution Pharmacological Effect
α-Carbon Indirect acting; resists oxidation by monoamine oxidase
β-Carbon Decreases central nervous system penetration
  Whereas hydroxyl (–OH): increases adrenergic activity
Amino group No substitution: α-adrenergic > β-adrenergic effects
  Larger group: β-adrenergic > α-adrenergic effects
  t-Butyl group: β2-adrenergic selective
  Methyl (–CH3) group: maximum α- and β-adrenergic effects
3-, 4- of aromatic ring Hydroxylation at 3- and 4-: increased α- and β-adrenergic effects
  Absence of hydroxylation (at one or both positions) prevents
degradation by catechol-O-methyltransferase.
Halogenation Enhances potency of neurotoxic properties of amphetamines by
selective action on the serotonin system
known as the synthetic cathinones. Specifically, the addition of this group
to amphetamine results in cathinone. The β-ketone group is responsible for
increased polarity, which decreases penetration of the blood–brain barrier.
PHARMACOKINETICS AND TOXICOKINETICS
Absorption
Amphetamines can be absorbed by intravenous, oral, intranasal, and inhala-
tional routes. Amphetamines are rapidly absorbed, with bioavailability that
ranges between 60% and 90% depending on the route of administration. Peak
serum concentrations are variable and are substance and route dependent.
Methamphetamine has peak serum concentrations in less than 15 minutes
when used via an intravenous (IV) or intranasal route and up to 180 minutes
when taken orally.
Distribution
After absorption, amphetamines are distributed to most compartments of
the body. Most amphetamines are also relatively lipophilic and readily cross
the blood–brain barrier. Amphetamines have large volumes of distribution,
varying from 3 to 5 L/kg for amphetamine, 3 to 4 L/kg for methamphet-
amine and phentermine, and to 11 to 33 L/kg for methylphenidate. Some
amphetamines such as pemoline have a small volume of distribution
(0.2–0.6 L/kg).
Metabolism
Amphetamines are eliminated via multiple pathways, including diverse
routes of hepatic transformation and renal elimination. For MDMA and
its analogs, N-dealkylation, hydroxylation, and demethylation are the
dominant hepatic pathways. Depending on the particular amphetamines,
active metabolites of amphetamines and ephedrine derivatives are formed.
N-demethylation of methamphetamine and MDMA result in the formation
of amphetamine and MDA, respectively.108 Dealkylation and demethylation
are mainly performed by CYP1A2, CYP2D6, and CYP3A4, as well as fla-
vin monooxygenase. Polymorphism of CYP2D6 in humans was recognized
because of the diversity of rates of p-hydroxylation of amphetamines. Since
its discovery, CYP2D6 polymorphism has been implicated in drug toxicity,
substance use and abuse, and lack of drug efficacy in selected individuals.146
Increased toxicity of amphetamines is a potential concern in patients with
decreased CYP2D6 activity. Although animals with CYP2D6 deficiency are
more susceptible to MDMA toxicity, limited studies in humans do not dem-
onstrate an association between mortality and CYP2D6 polymorphism.121
In general, because multiple enzymes and elimination pathways (including
renal) are involved in amphetamine metabolism, it is less likely that CYP2D6
polymorphism or drug interactions with CYP3A4 alone will significantly
increase toxicity. However, it is unclear if toxicity is enhanced when multiple
mechanisms for altering drug metabolism and kidney dysfunction are pres-
ent simultaneously.
Elimination
Renal elimination of the parent compound is substantial for amphetamine
(30%), methamphetamine (40%–50%), MDMA (65%), and phentermine
(80%). Amphetamines are bases with a typical pKa range of 9 to 10, and renal
elimination varies depending on the urine pH, with elimination increasing as
pH decreases.14 The half-life of amphetamines varies significantly: amphet-
amine, 8 to 30 hours; methamphetamine, 12 to 34 hours; MDMA, 5 to 10 hours;
methylphenidate, 2.5 to 4 hours; and phentermine, 19 to 24 hours. Repetitive
administration, which occurs typically during binge use, leads to drug accu-
mulation and prolongation of the apparent half-life and duration of effect.13,108
PATHOPHYSIOLOGY
Most complications associated with amphetamines are a result of an uncon-
trolled hyperadrenergic condition similar to that which occurs with other
sympathomimetics such as cocaine, except the duration of effect is typically
longer (Table 73–3). Most patients with acute amphetamine toxicity mani-
fest effects in the CNS and cardiovascular system. The majority of the specific
 CHAPTER 73 AMPHETAMINES 1103

TABLE 73 3 abstinence. This phenomenon of recurrent psychosis on reexposure is likely

related to a kindling phenomenon.112
Acute
Cardiovascular System Cardiac
Aortic dissection Cardiomyopathy is reported in chronic amphetamine users. Excessive cat-
Dysrhythmias echolamine exposure is likely responsible for their associated cardiomy-
Hypertension opathies, similar to that occurring in patients with pheochromocytomas
or chronic cocaine use.85,177 Some postulate that polymorphisms in CYP2D6
Myocardial ischemia
activity influences the risk of developing cardiomyopathy; however, a clear
Tachycardia
association is not demonstrated.164 Valvular heart disease and pulmonary
Vasospasm hypertension are associated with amphetamines taken for diet suppression.
Central Nervous System The mechanism of toxicity is incompletely understood but is likely do to
Agitation serotonergic activity occurs in carcinoid pathology. Specifically, alterations
Anorexia in serotonin reuptake transporter (SERT) activity is thought to play a signifi-
Bruxism cant role in the pathophysiology of both diseases, and drug effect at the 5HT2B
Choreoathetoid movements receptor is implicated in the development of valvular heart disease.103,144
Euphoria
Vascular
Headache
Necrotizing vasculitis of small- and medium-sized arteries occurs in associa-
Hyperreflexia tion with amphetamine use and affects multiple organ systems as described
Hyperthermia later. The etiology of the arteritis remains unclear. Although various con-
Intracerebral hemorrhage taminants associated with injection drug use are postulated as potential
Paranoid psychosis etiologies, in animal models, oral and IV amphetamine administration is
Seizures also associated with vasculitis, suggesting that this is a direct amphetamine
Other Sympathomimetic Symptoms effect.18,32,165
Diaphoresis
Chronic Central Nervous System Toxicity
Mydriasis
Chronic administration of certain amphetamines to animals alters dopa-
Nausea mine and serotonin transporter functions, depletes dopamine and serotonin
Tachypnea in the neuronal synapses, and produces irreversible destruction of those
Tremor neurons.16,56,139,140,145,180 The cause of neuronal toxicity is related to the genera-
Other Organ System Manifestations tion of oxygen free radicals, resulting in the generation of toxic dopamine and
Acute respiratory distress syndrome serotonin metabolites as well as neuronal destruction. Based on animal mod-
Ischemic colitis els, dose, frequency and duration of exposure, and ambient temperature affect
Muscle rigidity toxicity. Intact dopamine or serotonin transporters are necessary to produce
Rhabdomyolysis neurologic injury. Xenobiotics that inhibit transporter function appear to pre-
Laboratory Abnormalities vent neurologic injuries in animals.64 Although not as well studied as MDMA,
Creatine phosphokinase elevated studies of former methamphetamine users demonstrate impaired memory
and psychomotor functions, as well as corresponding dopamine transporter
Hyperglycemia
dysfunction and abnormal glucose metabolism on positron emission tomog-
Hyponatremia
raphy scans. However, species-specific susceptibility to neurologic injuries,
Leukocytosis the duration of effects in primates and humans, and functional consequences
Liver enzymes elevated of neurotoxicity in humans remain unclear and require further study.
Myoglobinuria
Chronic CLINICAL MANIFESTATIONS
Aortic and mitral regurgitation Acute and chronic toxicity of amphetamines are described next. Refer to
Cardiomyopathy the section Individual Amphetamines for effects specific to each individual
Dopaminergic and serotonergic neuron damage molecule.
Pulmonary hypertension Acute Toxicity
Vasculitis Central nervous system effects from acute amphetamine use include
anxiety, agitation, hallucinations, seizures, mydriasis, diaphoresis, and
hyperthermia.47,48,143 The pathophysiology of amphetamine-induced hyper-
effects are from excessive catecholamine release as opposed to direct effects thermia is multifactorial and includes increased catecholamine release,
from the amphetamines themselves. Additional organ-specific pathophysi- increased metabolic and psychomotor activity, and vasoconstriction-
ologic effects are described later. mediated impaired heat dissipation.106 Psychosis appears to be a more
prominent feature after amphetamine than after cocaine use.2 Intracerebral
Central Nervous System hemorrhage and cerebral infarction are also reported with amphetamine
Anxiety, agitation, and hallucinations are typical CNS findings that result use.49,84,110,129
from adrenergic stimulation. Choreoathetoid movements, often described Cardiovascular toxicity from acute amphetamine use involves hyperten-
as irregular jerking or twisting movements, are related to increased dopami- sion, tachycardia, and dysrhythmias. Reported dysrhythmias range from
nergic stimulation in the striatal area.88,101,107 Seizures are the direct result of premature ventricular complexes to ventricular tachycardia and ventricu-
amphetamine or occur secondarily to hyponatremia as reported with MDMA lar fibrillation.78 Other vascular complications reported with acute use
and certain synthetic cathinones.19 Psychosis, often a finding with acute include myocardial ischemia or infarction,113,173 aortic dissection,176 acute
use, is likely to recur with subsequent use, even after periods of prolonged respiratory distress syndrome,166,175 obstetric complications, fetal death,63,99
1104 PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
and ischemic colitis.77,82 Additional acute complications include meta-
bolic acidosis, rhabdomyolysis,50 acute kidney injury (AKI); acute tubu-
lar necrosis), and coagulopathy, often from uncontrolled agitation and
hyperthermia.39,70,170 Unless these systemic signs and symptoms are rapidly
reversed, multiorgan failure and death ensue.
Chronic Toxicity
Amphetamine users seeking intense “highs” go on “speed runs” for days to
weeks. Because of the development of tolerance, they use increasing amounts
of amphetamine during these periods, usually without much nutritional sus-
tenance or sleep, while attempting to achieve their desired euphoria.150 Acute
psychosis resembling paranoid schizophrenia occurs during these binges
and has contributed to both amphetamine-related suicides and homicides.51
A normal sensorium usually returns within a few days after discontinuation
of the drug. Typically, after such binges, patients sleep for prolonged periods
of time, feel hungry and depressed when awake, and often have amphet-
amine cravings.89,93
Compulsive repetitive behavior patterns from the use of amphetamines
are reported in humans and animals. Individuals pick at their skin, grind
their teeth (bruxism), or perform repetitive tasks, such as constantly clean-
ing the house or car. 3,4-Methylenedioxymethamphetamine users often
carry pacifiers to relieve bruxism and prevent tooth damage. Choreoathe-
toid movements, although uncommon, are reported with acute and chronic
amphetamine use.88,101,107
Necrotizing vasculitis is associated with amphetamine abuse. Angi-
ography typically demonstrates beading and narrowing of the small- and
medium-sized arteries (Fig. 8–29). Progressive necrotizing arteritis involves
multiple organ systems, including the brain, heart, gut, and kidney.18,32,92,165
Complications include cerebral infarction and hemorrhage, coronary artery
disease, pancreatitis, and AKI. Cardiomyopathy is also reported with acute
and chronic amphetamine abuse.156,182 Valvular disease and pulmonary
hypertension are reported when amphetamines such as fenfluramine,
dexfenfluramine, and phentermine are used for dieting.144,163
Finally, complications can result from IV drug use and from the associ-
ated contaminants. Contamination with microbials leads to human immu-
nodeficiency virus infection, hepatitis, and malaria. Bacterial and foreign
body contamination results in endocarditis, tetanus, wound botulism, osteo-
myelitis, and pulmonary and soft tissue abscesses.100
DIAGNOSTIC TESTING
The choice and extent of diagnostic tests should be guided by the history
and physical examination. In all patients with altered mental status, blood
specimens should be sent for glucose, blood urea nitrogen, and electrolyte
assays. An electrocardiogram should be obtained in all patients to screen for
tachydysrhythmias and coingestants, and continuous cardiac monitoring
should be initiated. A complete blood count, urinalysis, coagulation profile,
creatine phosphokinase, chest radiograph, computed tomography scan of
the head, echocardiogram of the heart, and lumbar puncture will be neces-
sary, depending on the clinical presentation.
Qualitative urine immunoassays are available for amphetamines, but sev-
eral considerations limit their utility in the management of acutely poisoned
patients. Although point-of-care urine tests are available, these tests rarely
contribute to management in the acute setting. A major limitation is the high
rate of false-positive and false-negative results common to the amphetamine
immunoassay. For example, many cold preparations contain pseudoephed-
rine, which is structurally similar and cross-reacts with the immunoassay.33,53
Likewise, selegiline, a selective monoamine oxidase type B inhibitor used for
the treatment of parkinsonism, is metabolized to amphetamine and meth-
amphetamine. Other common drugs that produce false-positive results
include bupropion, trazodone, amantadine, and certain antihistamines.21,119,123
Even a true-positive result only means that the patient has used certain
amphetamines within the past several days and does not distinguish remote
from acute use. False-negative results may occur with certain amphetamines
such as MDMA and cathinones, which are not recognized on standard
urinary drug testing.33,155 Utilization of such tests is often misleading and
rarely directly contributes to the acute management of patients. The gold
standard for drug testing, gas chromatography–mass spectrometry analysis,
can misidentify isomeric substances such as l-methamphetamine, which is
present in nasal inhalers, with d-methamphetamine, if performed by inexpe-
rienced personnel.10 In summary, the use of urine immunoassays should not
guide clinical management of patients who present with suspected toxicity
from amphetamines.
MANAGEMENT
The initial medical assessment of the agitated patient must include vital
signs, a rapid glucose determination, and a complete physical examina-
tion. Determination of core body temperature is essential to diagnose the
presence and degree of hyperthermia, which is a frequent and rapidly fatal
manifestation in patients with drug-induced delirium. Significant hyper-
thermia necessitates immediate interventions to achieve rapid cooling24,58
(Chap. 29). Some patients require temporary physical restraint to gain
pharmacologic control and prevent personal harm to themselves or others.
Physical restraints should be discontinued as soon as possible; prolonged
restraints result in rhabdomyolysis and continued heat generation. IV access
should be obtained so that IV sedation can be initiated. If IV access cannot be
obtained, it is necessary to attempt to administer intramuscular benzodiaz-
epines such as midazolam until definitive access is accomplished.
The most appropriate choice of chemical sedation is a benzodiazepine
because of the characteristic high therapeutic index, good antiepileptic
activity, and predictable pharmacokinetic properties. Benzodiazepines are
effective not only for the treatment of delirium induced by acute overdose of
cocaine, amphetamines, and other xenobiotics but also the delirium associ-
ated with ethanol and sedative–hypnotic withdrawal (Antidotes in Depth:
A26).44,61,122 Sedation should be titrated rapidly until the patient is calm. In
our clinical experience, cumulative benzodiazepine doses required in the ini-
tial 30 minutes to achieve adequate sedation will periodically exceed 100 mg
of diazepam or its equivalent (Table 73–4).
Antipsychotics, particularly potent dopamine antagonists such as halo-
peridol and droperidol, are frequently recommended as adjuncts for amphet-
amine-induced delirium. Potent blockade of dopamine receptors functions
TABLE 73 4
Agitation
Benzodiazepines (usually adequate for the cardiovascular manifestations)
Diazepam 10 mg (or equivalent) intravenously; repeat rapidly until the patient is calm
(cumulative dose periodically be as high as 100 mg of diazepam). An equivalent dose of
IM midazolam is recommended if IV access is not available.
Seizures
Benzodiazepines
Barbiturates
Propofol for status epilepticus (typically will require endotracheal intubation)
Hyperthermia
External cooling
Control agitation rapidly
Gastric Decontamination and Elimination
Activated charcoal for recent ingestions
Hypertension
Control agitation first
α-Adrenergic antagonist (phentolamine)a
Vasodilators (nitroglycerin, or nicardipine)
Delirium or Hallucinations with Abnormal Vital Signs
If agitated: benzodiazepines
a
Avoid β-adrenergic antagonists, especially with suspected cocaine toxicity.
IM = intramuscular; IV = intravenous.

to antagonize the psychiatric and psychomotor effects of amphetamines. In
experimental models, antipsychotics are not always as effective as benzodi-
azepines in treatment of amphetamine toxicity; however, results are mixed
regarding their safety and efficacy.40,45,61 Very little clinical data are available
evaluating antipsychotics in the management of amphetamine toxicity, but at
least one study in children demonstrates safety when antipsychotics are used
adjunctively with benzodiazepines.40,142 In our clinical experience, antipsychot-
ics are very effective for benzodiazepine-resistant methamphetamine toxicity
in children, particularly for symptoms of psychomotor agitation. However,
antipsychotics have several negative effects that must be taken into consider-
ation. Antipsychotics lower the seizure threshold, alter temperature regulation,
cause acute dystonia, and precipitate cardiac dysrhythmias. Hyperthermia and
seizures are potential life-threatening complications of amphetamine toxic-
ity, and the use of antipsychotics could worsen these outcomes. Additionally,
they do not interact with the benzodiazepine–GABA–chloride channel recep-
tor complex, which could aggravate the clinical outcomes related to occult or
concomitant cocaine toxicity and ethanol withdrawal.61,65,122 Based on these
concerns, benzodiazepines are recommended as first-line treatments in the
management of acute toxicity from amphetamines. In a patient without hyper-
thermia or seizure activity, in whom psychomotor or psychiatric agitation is
a predominant feature, adjunctive use of antipsychotics after benzodiazepine
administration is reasonable, particularly in children.
Rhabdomyolysis from amphetamines usually results from psychomotor
agitation and hyperthermia.141 Sedation, typically with benzodiazepines,
prevents further muscle contraction and heat production. External cool-
ing should be instituted for hyperthermia.95 Although some promote
dantrolene as potential treatment option for amphetamine-induced
hyperthermia, evidence is limited to case reports, predominantly involv-
ing MDMA.69 Strong evidence to support the use of dantrolene is limited
to cases of malignant hyperthermia, and side effects, including significant
respiratory muscle weakness, are reported.90 Given the potential harms
of dantrolene and limited supportive evidence, in contrast to known effi-
cacy of supportive measures, we do not currently recommended its use for
amphetamine-induced hyperthermia. Adequate IV hydration and cardio-
vascular support should maintain urine output of at least 1 to 2 mL/kg/h.
Although urinary acidification can significantly increase amphetamine
elimination and decrease the half-lives of amphetamine and methamphet-
amine,13,14 urinary pH manipulation does not decrease toxicity and instead
increases the risk of AKI from rhabdomyolysis by precipitating ferrihemate
in the renal tubules.37 Some patients with AKI, acidemia, and hyperkalemia
require urgent hemodialysis.
Amphetamine body packers, although uncommon, should be treated
similarly to those who transport cocaine (Special Considerations: SC5). Any
sympathomimetic symptom suggesting leakage of the packets requires sur-
gical intervention.172 Intravenous fluids, benzodiazepines, intubation, and
external cooling are often necessary to stabilize these patients.
INDIVIDUAL AMPHETAMINES
Methamphetamine
NH2
CH3
Amphetamine
NH2
H clinical effects, these xenobiotics are also used or distributed as MDMA
N in areas of MDMA popularity. Amphetamines sold as MDMA include 2CB,
CH3
CH3
Phenylethylamine
Methamphetamine
CHAPTER 73 AMPHETAMINES 1105
Methamphetamine is known by many names, including, but not limited
to, “yaba,” “speed,” “go,” “crack,” “uppers,” and “dexies.” The terms “crystal,”
“shard,” and “ice” refer to the crystalline form of methamphetamine. Meth-
amphetamine was first synthesized from ephedrine in Japan in 1893, soon
after the synthesis of amphetamine in 1887. Crystallized methamphetamine
was synthesized in 1919 through the reduction of ephedrine using red phos-
phorus. From the 1950s to the 1970s, there were multiple epidemics of meth-
amphetamine abuse in the United States.135 Methamphetamine is approved
by the FDA for the short-term treatment of attention deficit hyperactivity
disorder and obesity, and it is sold under the trade name Desoxyn as a
Schedule II drug. It is also prescribed for off-label use for refractory depres-
sion and narcolepsy.
The production of methamphetamine is relatively simple, requiring
minimal equipment and chemicals. There are many methods of methamphet-
amine production that initially use pseudoephedrine, ephedrine, or phenyl-2-
propanone (P2P). The primary ingredient of methamphetamine synthesis is
ephedrine, which can be hydrogenated into methamphetamine. The ephed-
rine method, using pharmaceutical grade -ephedrine, produces a product
with few contaminants that is stereochemically pure.46,132 Phenyl-2-propanone,
as an alternative ingredient, can be methylated into ephedrine and then trans-
formed into methamphetamine.23 Because of the strict control of ephedrine
and P2P, illicit chemists use phenylacetic acid to synthesize P2P.23,38 Lead
acetate, which is used as a substrate for the reaction, resulted in an epidemic
of lead poisoning associated with methamphetamine abuse in Oregon.3,120
Mercury contamination was also documented, although clinical mercury
toxicity has not been reported.23 Methamphetamine laboratories use many
potentially toxic xenobiotics, including phosphine gas, methylamine gas, chlo-
roform, and hydrochloric acid.4,79 These laboratories therefore pose a signifi-
cant health risk to law enforcement officers and the general public, causing
respiratory and ophthalmic irritation, headaches, and burns.29,154 Currently, the
sale of other potential amphetamine synthetic ingredients, such as hydrochlo-
ric acid, hydrogen chloride, anhydrous ammonia, red phosphorus, and iodine,
is also monitored and restricted in the United States.23,30
Methamphetamine exists as a chiral molecule with two isomers that
include levomethamphetamine and dextromethamphetamine. Although
the levorotatory form is devoid of CNS stimulatory properties, it retains
its vasoactive effects and is used in nonprescription nasal decongestant
inhalers. In the racemic mixture, the dextrorotatory form is solely respon-
sible for the stimulant effects observed with methamphetamines. Metham-
phetamine undergoes metabolism in the liver mainly to amphetamine and
4-hydroxymethamphetamine and has prolonged half-life of 19 to 34 hours,
although the duration of its acute effects can be greater than 24 hours.46
3,4-Methylenedioxymethamphetamine
H H
N O N
CH3
CH3 CH3
O
Methamphetamine Methylenedioxymethamphetamine
3,4-Methylenedioxymethamphetamine, also known as MDMA, was first
synthesized in 1912 and was rediscovered in 1965 by Shulgin. 3,4-Methylene-
dioxymethamphetamine is known as “ecstasy,” “E,” “Adam,” “XTC,” “Molly,”
and “MDM,” and it is commonly abused.128,174,178 Other amphetamines simi-
lar to MDMA include MDEA (“Eve”) and MDA (“love drug”). With similar
2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-
(3,4-methylenedioxyphenyl)-2-butanamine (MBDB).28,59 Typically, MDMA is
available in 50- to 200-mg colorful and branded tablets.
3,4-Methylenedioxymethamphetamine and similar analogs are so-called
entactogens (meaning “touching within”), capable of producing euphoria, inner
1106 PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
peace, and a desire to socialize.151 In addition, some psychologists used MDMA
to enhance psychotherapy until the Controlled Substances Act of 1986 placed
MDMA in Schedule I, thereby eliminating its medical use.127 People who use
MDMA report that it enhances pleasure, heightens sexuality, and expands con-
sciousness without the loss of control.66 Negative effects reported with acute
use included ataxia, restlessness, confusion, poor concentration, and impaired
memory.151 3,4-Methylenedioxymethamphetamine has about one-tenth
the CNS stimulant effect of amphetamine. Unlike amphetamine and meth-
amphetamine, MDMA is a potent stimulus for the release of serotonin.25,41,68
The concentration of MDMA required to stimulate the release of serotonin is
10 times less than that required for the release of dopamine or norepinephrine.
In animal models, the stereotypic and discriminatory effects of MDMA, and its
congeners can be distinguished from those of other amphetamines.25
The sympathetic effects of MDMA are mild in low doses. However,
when a large amount of MDMA is taken, the clinical presentation is simi-
lar to that of other amphetamines. Dysrhythmias, hyperthermia, rhab-
domyolysis, disseminated intravascular coagulation (DIC), and deaths
are reported.57,87,137 Significant hyponatremia is also reported with MDMA
use.1,22,73 3,4-Methylenedioxymethamphetamine and its metabolites
increase the release of vasopressin (antidiuretic hormone), and this is
thought to be related to the serotonergic effects.52 Furthermore, substan-
tial free water intake combined with sodium loss from physical exertion in
dance clubs increases the risk of the development of hyponatremia.
Molly is a purified or crystallized form of MDMA that is typically sold
as a powder rather than a pill and is taken orally. It gained popularity
because of what was perceived as a more rapid onset of symptoms and a
subtler offset or “come-down” period. Molly is also commonly viewed as a
safer form of MDMA because it is erroneously believed by users to contain
no adulterants. The use of Molly is associated with typical amphetamine
adverse effects.83 Although Molly is often sold on the street as pure MDMA,
Molly may contain various compounds including members of the 2C series,
amphetamines that have two methoxy groups and a halogen such as iodine
(2C-I) or bromide (2C-B).
A major concern with MDMA is its long-term effects on the brain. In
numerous animal models, acute administration of MDMA leads to the
decrease in SERT function and number. Recovery of SERT function takes
several weeks. Repetitive administration of MDMA ultimately results in
permanent damage to serotonergic neurons, typically causing injury to the
axons and the terminals while sparing the cell bodies.109,139 Some regenera-
tion of synaptic terminals occurs even with neuronal damage, but functional
recovery is incomplete. Intact SERT function is necessary for MDMA-
induced neurotoxicity. Xenobiotics that inhibit the reuptake of serotonin
prevent MDMA-induced neurotoxicity in animals. Animal data suggest that
MDMA induces hydroxyl free radical generation and decreases antioxidants
in serotonergic neurons.147 3,4-Methylenedioxymethamphetamine itself is
not the ultimate neurotoxin; rather, its metabolites 3-methyldopamine and
N-methyl-α-methyldopamine appear to be responsible in animals.114 When
antioxidants are depleted, neuronal damage occurs.
Para-methoxyamphetamine and Para-methoxymethamphetamine-
Monomethoxy Derivatives
NH2
NH2
H3C
CH3
CH3 O
Amphetamine Para-methoxy-N-methylamphetamine (PMA)
H H
N
N
CH3 CH3
CH3 H3C CH3
O is a popular drug of abuse.168 Bupropion, a popular pharmaceutical licensed
Methamphetamine Para-methoxy-N-methylamphetamine (PMMA)
Para-methoxyamphetamine (PMA) is the 4-methoxylated analog of amphet-
amine, and para-methoxy-N-methylamphetamine (PMMA; methyl-MA) is
the 4-methoxy analog of methamphetamine. Para-methoxyamphetamine
was first produced in 1973 and sold as a hallucinogen for a short period of
time and then reemerged in the 1990s. Para-methoxy-N-methylamphetamine
soon appeared after PMA, with multiple reports of death also emerging dur-
ing that time.12,81,91 Para-methoxyamphetamine and PMMA are commonly
found as tablets or capsules sold as MDMA or “ecstasy.” Although the effects
of PMA and PMMA mimic some aspects of MDMA and methamphetamine,
unique properties of PMA and PMMA make them considerably more lethal,
earning the street name “death.” More than 100 fatalities and severe poison-
ings attributed to PMMA and PMA are reported in North America, Australia,
and Europe.94,98,102,105
Methoxy ring substitution of amphetamine or methamphetamine at the
3 or 4 positions (para substitution is the most common) yields PMA and
PMMA derivatives that have significantly less sympathomimetic activity
than amphetamine but very potent serotonergic activity.35,158 Both PMA and
PMMA inhibit reuptake of serotonin and inhibit monoamine oxidase A found
centrally and peripherally. The methoxy ring substitution is also responsible
for poor penetration of the blood–brain barrier.8,54
Para-methoxyamphetamine and PMMA poisoning results in autonomic
hyperactivity similar to that observed with other amphetamines, namely,
hypertension, tachycardia, and agitation. Poor blood–brain barrier penetra-
tion results in a delayed onset of CNS effects and overall a comparatively
weak euphoric effect. These properties often lead users to repeat doses,
resulting in severe toxicity and the seemingly high mortality rate.
Cathinones (Methcathinone, Methylenedioxypyrovalerone,
and Mephedrone)—”Bath Salts”
O
H H
N N
CH3 CH3
CH3 CH3
Methamphetamine Methcathinone
Cathinone (2-amino-1-phenyl-1-propanone) is a naturally occurring sub-
stance found in the leaves of the Catha edulis (khat) plant. Also known as
guat and gat, the fresh leaves and stems are commonly used as a stimulant
in Africa and the Middle East. The plant form contains numerous amphet-
amines in minute quantities, but the primary active ingredient is cathi-
none. As the leaves age, cathinone is degraded to cathine, which has about
one-tenth the stimulant effect of -amphetamine. Imported fresh khat
must be consumed within a week, or much of its potency is lost. The pri-
mary effects of khat are increased alertness, insomnia, euphoria, anxiety,
and hyperactivity. Khat chewing is linked to cardiac and gastrointestinal
(GI) disease.124,125
The syntheses of cathinone derivatives were reported in the early 1920s,
with the production of methcathinone in 1928 and mephedrone in 1929.
Methcathinone, the methyl derivative of cathinone, was used in Russia as
an antidepressant in the 1930s and 1940s. Also known as “Cat” and “Jeff,”
cathinone was used recreationally, historically most often in countries
formerly part of the Soviet Union. Various synthetic cathinones, including
mephedrone and methylenedioxypyrovalerone (MDPV), have gained pop-
ularity in both the United States and Europe in recent years.7 Increased
popularity of synthetic cathinones is likely be due to a combination of media
attention and widespread Internet availability.133,149 Many other synthetic
cathinones produced include methylone, mephedrone, butylone, MDPV,
dimethylcathinone, ethcathinone, ethylone, 3-,4-fluoromethcathinone,
and α-pyrrolidinovalerophenone. α-Pyrrolidinovalerophenone (1-phenyl-
2-(pyrrolidin-1)-ylpentan-1-one), sold on the street as “flakka,” in particular
for treatment of depression and smoking cessation, is the only medicinally

used cathinone.111 Sustained-release bupropion overdoses are associated
with delayed toxicity. Serious toxicity in overdose, including seizures and
refractory dysrhythmias requiring extracorporeal membrane oxygenation as
well as fatalities, are reported.75,157
The synthetic cathinones differ structurally from other amphet-
amines by the addition of a ketone at the β position. The β-ketone group
is responsible for increased polarity, which decreases penetration of the
blood–brain barrier. Cathinones possess amphetamine-like properties
and have sympathomimetic effects, although as a group, they are con-
sidered less potent. Both the US Poison Control Centers and the Toxi-
cology Investigator’s Consortium Registry (ToxIC) data report common
adverse effects to include agitation, tachycardia, hallucinations, and a
general sympathomimetic toxidrome.55,155 Some synthetic cathinones
cause hyponatremia, although the mechanism is not clear and may dif-
fer from that of MDMA.11,26,27,104,130 Reported complications include com-
partment syndrome, DIC, AKI, cardiomyopathy, myocardial infarction,
seizures, and sudden cardiac death.55,96,116,138,148,183 An irreversible Parkinson
syndrome was also described in chronic users of IV methcathinone that
was manufactured with the use of potassium permanganate as an oxidiz-
ing agent. In one case series, T1-weighted magnetic resonance imaging
showed symmetric hyperintensity in the globus pallidus, substantia
nigra, and innominata in all active methcathinone users, characteristic
of manganese poisoning. These cases were also confirmed with elevated
whole-blood manganese concentrations.159
Synthetic cathinones are often sold as “bath salts” or “plant food” and
labeled as “not for human consumption” to circumvent controlled substances
legislation. The legal status differs among countries and changes over time.
In the United States, the synthetic cathinones were initially unscheduled but
were made illegal for human consumption under the Federal Analogue Act
of 1986. In 2011, the Drug Enforcement Administration used its emergency
scheduling authority to enact temporary control, making possession or sale
of methylenedioxypyrovalerone, methylone, and mephedrone illegal. This
was later written into permanent law. In 2014, an additional 10 synthetic
cathinones were given temporary Schedule I status.
Bromo-dragonFLY
O lucinogenic properties. The 2C series differs in that they lack an α-carbon
NH2
NH2
CH3
CH3
Br
O stitutions at positions 2,4 and 5 on the phenyl ring. The compound 2C-I is an
Amphetamine Bromo-dragonFLY
1-(8-Bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-aminopropane, also known
as Bromo-dragonFLY (BDF), was first synthesized in 1998. Bromo-
dragonFLY was named after its superficial structural resemblance to a
dragonfly, similar to its less potent predecessor, the dihydrofuran series
nicknamed FLY. Bromo-dragonFLY is a member of a new class of benzodi-
furans, which were used as potent tools for investigation of the serotonin
receptor family. Benzodifurans were also briefly investigated as potential
antidepressants.179
Structurally, BDF is closely related to other phenylethylamines such as
DOB and 2C-B but contains two furan rings on either side of the benzene
ring, creating a fully aromatic tricyclic structure. There are several similar
compounds to BDF, differing by substitution of the bromine atom with
other entities. Bromo-dragonFLY exists as R- and S-enantiomers, which
are both biologically active. The R-enantiomer is considered more potent,
with a significant hallucinogenic effect mediated primarily through the
5-HT2A serotonin receptor (also with affinity for the 5-HT2B and 5-HT2C
serotonin receptors).126
Bromo-dragonFLY use is associated with deaths in Europe and the
United States. Reports demonstrate delayed complications owing to severe
peripheral vasoconstriction and limb ischemia. Such complications likely
result from BDF’s potent serotonergic properties.5,34,41,167,179
CHAPTER 73 AMPHETAMINES 1107
2,5-Dimethoxy-4-Methylamphetamine and
2,5-Dimethoxy-4-Iodoamphetamine
OCH3
NH2
NH2
CH3
CH3 H3C
OCH3
Amphetamine 2,5-Dimethoxy-4-methylamphetamine
2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP, which
stands for “serenity, tranquility, and peace,” emerged in the 1960s as a halluci-
nogen. It was noted for its delayed onset of action and duration of effect, which
resulted in a short-lived appearance. 2,5-Dimethoxy-4-iodoamphetamine
(DOI) is another potent hallucinogen, previously sold as a substitute for lyser-
gic acid diethylamide, or LSD.
Dimethoxy amphetamine derivatives are structurally characterized by
methoxy ring substitution at the 2 and 5 positions on the aromatic ring, with
varying substitution of hydrophobic moieties at the 4 position. 2,5-Dimethoxy-
4-methylamphetamine and DOI are both serotonin receptor agonists with
selectivity at the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. Because of
this selectivity, DOM and DOI are often used in scientific research involving
study of the 5-HT2 receptor subfamily. 2,5-Dimethoxy-4-methylamphetamine
exists as a chiral molecule, with the R-(-)-enantiomer considered the more
potent.15
Potent hallucinogenic effects and dysphoria characterize the use of DOB
and DOI, with minimal sympathomimetic effects. These symptoms can often
be delayed with a prolonged duration of effect, sometimes refractory to the
use of benzodiazepines. Reversible vasospasm with the use of dimethoxy
amphetamine derivatives is reported.9,20
The 2C-Series and N-2-methoxybenzylphenylethylamines
The 2C-series and its derivatives are similar in structure and function DOM
and DOI as all are dimethoxy phenylethylamine derivatives with potent hal-
methyl group and are thus not true amphetamines in structure.
The first of this series 2C-B was initially intended for psychotherapy, how-
ever, it fell out of favor because of GI side effects and limited entactogenic
effects. Multiple other 2C compounds have been developed by altering sub-
iodo-substituted dimethoxy phenylethylamine popularized in recent years
as “smiles.” Reported clinical effects of this series include sympathomimetic
effects, delirium, hallucinations, and psychosis.42
2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]etha-
namine (2C-I-NBOMe, N-Bomb) was discovered in 2003, along with other
similar NBOMe compounds. It possesses strong 5-HT2A agonism and was
initially used as a pharmacologic tool to study 5-HT2A receptors. 2C-I-
NBOMe is synthesized by N-benzyl substitution of 2C-I and is currently
used recreationally as an LSD alternative. The high potency of NBOMe
compounds compared with 2C-I allow efficacy in microgram doses, with
subsequent potential for accidental overdose. NBOMes are used by all
routes, but poor oral bioavailability limits oral use.71,118 Reported clinical
effects include euphoria, hallucinations, and sympathomimetic effects.
Deaths are reported.118,169
SUMMARY
■ Novel amphetamines, often created to evade designer drug laws, con-
tinue to increase dramatically throughout the United States.
■ e extensive knowledge of the modi cations to the existing phenyl-
ethylamine backbone allows clinicians to predict the e ects of the
amphetamines. ese e ects are attributed to variable degrees of selec-
tivity a ecting dopamine, norepinephrine, and serotonin.
1108 PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY
■ Many complications associated with amphetamines are similar to
those of cocaine, such as agitation, hyperthermia, rhabdomyolysis,
myocardial ischemia, and cerebral infarction.
■ e management of patients with acute toxicity of any of the amphet-
amines includes supportive care, with the judicious use of benzodiaze-
pines and anticipation of complications of adrenergic and serotonergic
toxicity such as hyperthermia and rhabdomyolysis.
Acknowledgment
William K. Chiang, MD, contributed to this chapter in previous editions.
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