SYMPOSIUM:
BEHAVIOR
MODIFICATION
BY DRUGS
PEDIATRICS, Vol. 49, No. 5, May 1972
I. PHARMACOLOGY
OF
THE
AMPHETAMINES
Ross J. Baldessarini, M.D.
From the Laboratory of Neurophar-inacology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
MONG the drugs currently under study for children with presumptive “mini-mal brain disorders” and hyperactivity, the amphetamines are the best known and most extensively investigated by neuropharma-cologists. Amphetamines (Fig. 1) are sym-pathomimetic phenylethylamines, charac-terized by methyl-group substitution at the a-carbon of the side-chain of the molecule, which produces optical isomerism ( dextro-versus levo-rotatory forms ) . Other com-pounds in this class have alkyl substituents
(
R, Fig. 1) on the amino-nitrogen atom, or halogen atoms on the benzene ring.Sympathomimetic drug substances as natural products have been known for at least 5000 years. In 1887, Nagai’ isolated
ephedrine (
N-methyl4-hydroxy-amphet-amine ) from the Chinese herbal folk rem-edy, MaHuang (Ephedra vulgaris). In the same year, Edelean& prepared amphet-amine as a volatile liquid and in 1910, Bar-ger and Dale noted its sympathomimetic properties.2 In 1919, Ogata1 prepared N-methyl-amphetamine (Methedrine). Many other analogs of the sympathomimetic natu-ral products, ephedrine and epinephrine
(
“adrenalin” ) were synthesized in the early1900’s.24 Ephedrine was introduced into
Western medicine in the 1920’s by Chen and Schmidt.4
In the late 1920’s Alles5 prepared several
synthetic substitutes for ephedrine, which
led to the introduction of Benzedrine
(
d,1-amphetamine sulfate ) inhalation therapy for bronchodilation and nasalmu-cosal constriction. Alles recognized the
cen-tral nervous system (CNS) stimulating ac-tions of amphetamines and soon after their introduction they were used successfully for
the treatment of narcolepsy by Prinzmetal and Bloomberg.65 The amphetamines were also used as early as the 1930’s by Bradley6 in the treatment of behavioral disorders in children.
Although the amphetamines have ceived attention from pharmacologists for a longer time than any other drug used in
neuropsychiatry, the present understanding
of their actions is still limited. Information
about the metabolism of the amphetamines and their chemical interactions with central neurons is available and various aspects of the subject have been reviewed
previ-ously.712 However, the relationships
be-tween the metabolic and behavioral effects
of the drugs remain somewhat unclear.
METABOLISM
The amphetamines are usually adminis-tered orally as their soluble suffate or phos-phate salts. They are readily absorbed, distributed widely13 and are particularly concentrated in the kidney, lung, and brain.14 Effects of an oral dose of
ampheta-mine upon the CNS appear within about 30 minutes and usually last for several hours. The lack of charged groups other than the amino nitrogen and the presence of a lipophilic a-methyl group facilitate the pas-sage of amphetamines through the blood-brain diffusion barrier. In man, large
amounts of unmetabolized amphetamine or
acidic, deaminated metabolites are excreted during the first 24 hours after an oral dose, and lesser amounts are detectable in the
urine for 2 to 3 days.1518 Amphetamine is a
weak base and at physiological pH it exists mainly as the charged [RNH3J mole-cule, which is poorly resorbed in the renal
Based on a lecture to the American Academy of Pediatrics, Chicago, Illinois, October 21, 1971.
Partially supported by U.S. Public Health Service
(
NIMH) Grant MH-16674.The author is a recipient of Research Scientist Development Award
(
NIMH)
KO2-MH-74370.ADDRESS FOR REPRINTS: Laboratory of Neuropharmacology, Massachusetts General Hospital, Boston,
tubules; acidic urine favors the excretion of the charged form of the amine.’517
In man, about 30 to 40% of a dose of am-phetamine is excreted as such without
me-tabolism.13,15 The fate of amphetamine is
similar to that of many drugs in that its metabolic products are more highly oxi-dized, more polar, and thus more readily excreted. Historically, study of the metabo-lism of the amphetamines led to the description of important detoxification mechanisms in hepatic microsomes. Thus, Axelrod19 found that amphetamine is oxida-tively deaminated by rabbit liver
micro-somes, although it is a poor substrate for
monoamine 20 Oxidative
deamina-lion of amphetamine is a relatively impor-tant pathway in man since free or conju-gated benzoic acid in urine can account for at least 20% of an administered dose of amphetamine.’ Amphetamine and other
aro-matic compounds may also undergo p-hy-droxylation of the benzene ring by the ac-tion of microsomal enzymes.21 Furthermore, hydroxylation of the side-chain (13-position) appears to occur uniquely within sympa-thetic nerve endings.22 Ring and side-chain
hydroxylation of the amphetamine mole-cule occur in man to a more limited extent than in other species,’3’ although wide in-dividual differences occur.17 It has been suggested that p-hydroxy-amphetamine and its Il-hydroxylated congener, p-hydroxy-norephedrine may be inactive analogs of endogenous catecholamines, or so-called
“false neurotransmitter” products.2426
Whether such metabolites are important in
the action of the amphetamines is still open to question.
BIOCHEMICAL ACTIONS
The actions of the amphetamines are still a subject of some controversy. There is some evidence that amphetamines may stimulate cholinergic neural systems in the brain.27’28 It is also known that certain halo-genated amphetamines have profound effects on the metabolism of serotonin in the brain.29 Nevertheless, the most striking and most thoroughly investigated effects of
the ordinary unsubstituted amphetamines have been their interactions with the cate-cholamine-containing neural systems. The amphetamines exert a variety of peripheral sympathomimetic effects.2’3’5’8 and their toxic effects include alterations of blood pressure and cardiac rhythm.8 More re-cently, attention has focused on the actions of the amphetamines on catecholamine-containing neurons in the CNS.7 It is very probable that norepinephrine and dopa-mine may function as central
neurotrans-mitters.7’30’3’ Catecholamine neurons occur
throughout the reticular activating system, diencephalon, basal ganglia, limbic system, and cerebral cortex.7’30’31 Important struc-tural and metabolic features of central
cate-cholamine-containing neurons are
summa-rized in Figure 2.
The actions of many indirect sympatho-mimetic amines, including the amphet-amines, has usually been ascribed to their ability to “release” or displace catechola-mines from sympathetic nerve terminals.32
Thus, amphetamine can deplete stores of
norepinephrine in the heart as well as the
brain.24,25,33 The ability of amphetamine to
displace or release endogenous dopamine from the locally perfused caudate nucleus,3 or to release selectively previously stored labelled catecholamines during perfusion of various areas of the brain has been
re-ported.123536 Amphetamine itself does not
enter adrenergic neurons readily37 and the time-course of depletion of stores of norepi-nephrine correlates better with the accumu-lation of hydroxylated metabolites (at least in the rat ) than with the presence of unme-tabolized amphetamine.2425 Although the stimulant action of the drug ends long be-fore tissue concentrations of norepinephrine return to normal,24,25 the levels of
transmit-ters tell very little about the dynamic as-pects of synaptic function. It is particularly important to consider the dynamics of me-tabolism of the catecholamines since their levels are regulated by potent conservative processes which include (Fig. 2) a
vigor-Fic. 1.Structure of amphetamine.
696
‘9
R
I
NH
ous reuptake and protective presynaptic
ye-sicular storage ni739 Amphet-amine appears to interact with themetabo-lism of catecholamines in several ways in addition to its effects on resting levels. Thus, amphetamine, particularly the d-en-antiomer, has potent inhibitory effects on the reuptake process,7’941 which is be-lieved to be the major means of inactivating released catacholamine neurotransmitter
7, 39 \Vhen the transmitter is “re-leased” by amphetamine, much of it
ap-pears to reach an extraneuronal location42
where presumably it may stimulate post-synaptic “receptor” sites (Fig. 2) . Finally, amphetamines can act as inhibitors in mono-amine oxidase (MAO ), although the sig-nificance of this inhibitory effect is un-clear.7’43
An important question is whether cate-cholamines are required for the action of amphetamine. There is no convincing evi-dence that amphetamine itself at ordinary doses has a direct post-synaptic action at adrenergic receptors. While amphetamine does produce changes in electrical activity when applied directly to central neurons by micropipettes, these effects are apparently mediated by the release of endogenous amines, as they are abolished by
pretreat-ment with reserpine,44 a drug which
pro-foundly depletes amine levels in the brain by preventing intraneuronal storage.7 There is also evidence that depletion of catechola-mine levels in the brain by pretreatment
with a potent inhibitor of synthesis ( a-methyl-p-tyrosine ) can block both central and peripheral effects of amphetamines.’46
It is clear that nearly all of the actions of amphetamine upon the metabolism of
cate-cholamines at nerve terminals would be
cx-pected to enhance synaptic transmission. Thus, release, inhibition of catabolism, pre-venting reuptake should all act coopera-tively to increase the availability of
trans-mitter molecules to their post-synaptic sites
of action (Fig. 2).
PHYSIOLOGICAL AND BEHAVIORAL ACTIONS
The physiology of the central catechola-mine-containing neuronal systems is still poorly understood. It is likely that dopa-minergic transmission is important in the function of the basal ganglia,31’48 and it may also be involved in the release of the pituitary-hormone releasing factors in the hypothalamus. Norepinephrine-containing
neurons may participate in the central control of various visceral, autonomic and affective functions, and in the regulation of consciousness and alertness mediated by the ascending reticular activating system.47
Some of the earliest hypotheses concern-ing the actions of amphetamines proposed that the behavioral and electroencephalo-graphic arousal produced by these drugs are mediated by the reticular activating system.5052 More recently,
norepinephrine-containing neural systems have been
impli-cated in positively reinforced behaviors, in-eluding self-stimulatory behavior in aninials with electrodes implanted in the midbrain-diencephalon.lI It is believed that ascend-ing norepinephrine-containing neurons which pass through the diencephalon into the limbic system by the median forebrain bundle may support appetitive and drive states and may be involved in an affective reinforcement function which may help to consolidate learning.12 Amphetamine may
Tyrosine
Adrenerg Ic
receptor
COMT
+AMe
I
C I RCULAT
ION
effects in man53 in that increases in
perform-ance are most readily detectable under conditions of fatigue or suboptimal perfor-mance. The potency of d-amphetamine upon most behaviors is from 3 to 10 times that of the 1-isomer.8’12’4’
While it is tantalizing to speculate about the central actions of the amphetamines in
hyperkinetic children, too little is known about the physiology of central “catechola-minergic” neural systems to support such speculation. Another complicating factor is that it is not clear that one can simply equate man with laboratory animals and even less clear that hyperkinetic children
PRESYNAPTIC
N EU RON
are like other children or adults in their re-sponse to the amphetamines. For example,
many children with behavioral disorders
have marked tolerance to central stimulants and the drugs may even have paradoxical “quieting” effects in them,6’54 although sys-tematic comparisons of responses to am-phetamines in hyperactive children and normal children or adults are not available and would be difficult to justify.
TOXICITY
The amphetamines are reasonably safe
drugs when used appropriately, and
prob-lems of toxicity related to controlled
mcdi-POSTSYNAPTIC
NEURON
FIG. 2. Model of a synapse mediated by catecholamines : In the presynaptic terminal synthesis occurs by
tyrosine hydroxylation (rate-limiting step), dihydroxyphenylalanine (dopa) decarboxylation and in
norepinephrine-containing neurons, dopamine--hydroxyIation. The transmitter products, dopamine or
norepinephrine
(
NE)
, are stored in vesicles and released into the synaptic cleft by depolarizing actionpotentials, a process which requires calcium ions. Effects are exerted at a post-synaptic “receptor” site and released transmitter is inactivated by reuptake into the pressuaptic neuron. Some excess amine may
also be metabolized by intraneuronal mitochondrial monoamine oxidase
(
MAO)
and bycatechol-0-methyl-transferase
(
COMT) with its co-factor, S-adenosylmethionine (AMe). Most molecules whichreach the circulation are both oxidatively deaminated and 3-0-methylated. Amphetamine is likely to en-hance transmission at such synapses by displacing or “releasing” transmitter directly
(
or by indirectstimulation of neural circuits), by interfering with the reuptake process and possibly by inhibiting MAO
698
PHARMACOLOGY
OF AMPHETAMINES
cal use in narcoleptic patients and hyperac-live children, even after several years, are unusual.1,8,D,54 Anorexia, mild gastrointesti-nal disturbances, and insomnia can occur early in treatment, but tolerance to these side effects usually develops. Children occa-sionally develop mild tremor, peculiar
man-nerisms and withdrawal or drowsiness, and
rare cases of overt paranoid psychosis in children have been reported. Accidental or intentional overdosage can produce vari-ous toxic effects, most of which can be inter-preted as exaggerations of the usual periph-era! sympathomimetic and central effects of the amphetamines. Symptoms may include
restlessness, irritability, tremor and ataxia,
fever, confusion, delirium or panic, and car-diovascular dysfunctions such as headache, cardiac arrhythmias, and hypertension followed by hypotension and cardiovascu-lar collapse, particularly after chronic abuse. Death is often preceded by seizures and coma, and is usually associated with se-vere hypertension, hyperpyrexia, and gross or petechial intracranial hemorrhage.8’55
Toxicity is somewhat unpredictable by dosage, and tolerance to huge doses
(
more than 1,000 mg per day) can develop withchronic abuse. Rarely, significant toxicity
may occur after doses as low as 10 to 30 mg,
particularly after intravenous
administra-tion. The lethal dose of dextroamphetamine sulfate in man is not known accurately; it
has been estimated to be about 20 to 25 mg per kg of body weight, although it may vary from 10 to 85 mg/kg in laboratory
an-imals.1,SS,SG Poisoning in children can be
catastrophic and fatalities may be expected after doses as low as 5 mg/kg in a young child.1 The treatment of acute
amphet-amine poisoning usually includes acidifica-lion of the urine and the use of
chiorproma-zine57 or other neuroleptic drugs, which may have a blocking action upon catechola-mine receptors and may prevent hyperther-mia. Rapidly acting agents which block a-adrenergic receptors, such as phenoxyben-zamine or the shorter acting phentolamine, given parenterally, may also have a place in the management of hypertensive emergen-cies.8’57
The chronic abuse of the amphetamines can lead to many of the problems encoun-tered acutely, but in addition hypotension8 and psychosis58’59 are seen. While several
structural analogs of the amphetamines are
more potent hallucinogens,#{176} the psychosis usually encountered is produced by
am-phetamine itself among youthful abusers
after prolonged consumption of 100 to 500
mg a day and particularly following re-peated intravenous self-administration of amphetamine, although psychosis can also
occur in middle-aged women1 and rarely
even in children during medically pre-scribed uses of amphetamine. The com-mon clinical picture is a paranoid psychosis with a clear sensorium, remarkably similar to idiopathic paranoid psychoses, with per-secutory or grandiose delusions, hallucina-lions of various types, some confusion, and occasionally aggressive and destructive ex-citement. Often, following such experiences or after milder “highs,” a “crashing down” may occur, with depression, fatigue, and even coma.1 The psychoses are usually self-limited and disappear rapidly within a few days after discontinuation of the drug, al-though phenothiazines may be helpful in the management of the acute stages of the
illness. An interesting feature of the
psycho-sis is that peculiar repetitive mannerisms of the extremities or mouth and jaw are quite common, and are very similar to the behav-ioral stereotypes produced by amphet-amines in animals, which are believed to result from altered function of dopamine-containing neurons in the basal ganglia.416l
The clinical indications for the use of the amphetamines except for narcolepsy and for selected cases of childhood behavioral disorder are very limited.8 Nevertheless, the potent central stimulating actions of the
amphetamines in adults has led to
wide-spread abuses, including excessive manu-facture and active “black market” trading
of the drugs during and since World War
11,1,9,11 their current abuse by youthful
ARTICLES
females.62 There is some disagreement whether the habitual use of amphetamines produces a true “addiction.” The disagree-ment is partly semantic, and the degree of social and behavioral dysfunction associ-ated with the chronic abuse of the amphet-amines can be fully as serious as that associ-ated with more classical addicting agents such as alcohol or heroin: in some cases there are clear tendencies to use the drug in increasing doses, to return to the habit following withdrawal, and for life to
be-come pervasively involved with the use of the drug,”63 When more narrow pharmaco-logical definitions of addiction are consid-ered, there is evidence that tolerance and some degree of physical dependence do oc-cur.63’#{176}4However, the abstinence syndrome following withdrawal from even huge doses of amphetamine is relatively mild, com-pared with that of the central depressant addictants”6 Nevertheless, the lethargy and depression which occur on withdrawal and the electroencephalographic changes during sleep (a “rebound” of previously
suppressed “rapid eye movement” sleep )64
can be considered signs of true, if mild, physical dependence. Fortunately, toler-ance is unusual in the responses of patients to amphetamine for narcolepsy or hyperki-nesis, and furthermore the drug has been discontinued abruptly in such patients without ill effects.l,46,63
SUMMARY
The pharmacology of the amphetamines has been studied for several decades. There is now a great deal of information about their tissue distribution and catabolism, largely by enzymatic oxidative processes. The most clearly characterized actions of the amphetamines occur at catecholamine-containing nerve terminals and tend to
en-hance the availability of the transmitter to
post-synaptic receptors. The actions of the
drugs in the CNS include stimulation of the
ascending reticular formation of the brain-stem, and probably enhancement of the
ac-tivity of a behavior reinforcement system
mediated by the median forebrain bundle. Toxic effects of amphetamine include
ap-parent interactions at the basal ganglia to produce stereotyped behaviors in animals and man. All of these actions might involve catecholaminergic synaptic transmission sys-tems. Under careful, controlled medical supervision the amphetamines are
remark-ably safe, although in excessive doses they
can produce severe toxic, sympathomimetic and psychotic effects and can be lethal. They are subject to gross abuses, and to habitua-tion. Tolerance develops to some of their
actions, but usually not to their legitimate
and rational uses in narcolepsy and
hyper-kinesis. Withdrawal symptoms are relatively
minor.
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CORRECTION
An error was made in Doctors
J.
C. Jacobs and M. E. Miller’s article, “Fatal Familial Leiner’s Disease: A Deficiency of the Opsonic Activity of Serum Complement,” in theFebruary, 1972 issue of PEDIATRICS. The captions for figures 1-3 should have read, “Patient
