32

C H A P T E R

Drugs of Abuse
Christian Lüscher, MD

C ASE STUDY

A 15-year-old high school student is brought to the emergency When questioned by the intern, he reports that space-
department after his parents found him in his room staring at cookies were served at the party. He also says that smoking
the ceiling and visibly frightened. Earlier that evening, he marijuana has become a habit (three to four joints a week)
attended a party but was depressed because his girlfriend just but denies consumption of alcohol and other drugs.
broke up with him. Jerry is failing this year at school and has How do you explain the state he was found in? What is
stopped playing soccer. His parents are also worried about a the difference between hashish and marijuana? What may
change in his behavior over the last few months. He has lost be the link to his poor performance at school? Are all drug
interest in school, at times seems depressed, and tells his par- users necessarily using several drugs?
ents that his pocket money is not sufficient.

Drugs are abused (used in ways that are not medically approved) of drug abuse—it can also occur with many classes of non-
because they cause strong feelings of euphoria or alter percep- psychoactive drugs, eg, sympathomimetic vasoconstrictors and
tion. However, repetitive exposure induces widespread adaptive bronchodilators, and organic nitrate vasodilators. Addiction, on
changes in the brain. As a consequence, drug use may become the other hand, consists of compulsive, relapsing drug use despite
compulsive—the hallmark of addiction. negative consequences, at times triggered by cravings that occur in
response to contextual cues (see Box: Animal Models in Addiction
■ BASIC NEUROBIOLOGY OF Research). Although dependence invariably occurs with chronic
exposure, only a small percentage of subjects develop a habit, lose
DRUG ABUSE control, and become addicted. For example, very few patients who
receive opioids as analgesics desire the drug after withdrawal. And
DEPENDENCE VERSUS ADDICTION only one person out of six becomes addicted within 10 years of
first use of cocaine. Conversely, relapse is very common in addicts
There is a conceptual and mechanistic separation of “dependence” after a successful withdrawal when, by definition, they are no
and “addiction.” The older term “physical dependence” is now longer dependent.
denoted as dependence, whereas “psychological dependence” is
more simply called addiction.
Every addictive drug causes its own characteristic spectrum of ADDICTIVE DRUGS INCREASE THE
acute effects, but all have in common the characteristic that they LEVEL OF DOPAMINE: REINFORCEMENT
induce strong feelings of euphoria and reward. With repetitive
exposure, addictive drugs induce adaptive changes such as toler- To understand the long-term changes induced by drugs of abuse,
ance (ie, escalation of dose to maintain effect). Once the abused their initial molecular and cellular targets must be identified. A
drug is no longer available, signs of withdrawal become apparent. combination of approaches in animals and humans, including
A combination of such signs, referred to as the withdrawal syn- functional imaging, has revealed the mesolimbic dopamine system
drome, defines dependence. Dependence is not always a correlate as the prime target of addictive drugs. This system originates in

575
576 SECTION V Drugs That Act in the Central Nervous System

the ventral tegmental area (VTA), a tiny structure at the tip of the As a general rule, all addictive drugs activate the mesolimbic dopa-
brainstem, which projects to the nucleus accumbens, the amygdala, mine system. The behavioral significance of this increase of dopa-
the hippocampus, and the prefrontal cortex (Figure 32–1). Most mine is still debated. An appealing hypothesis is that mesolimbic
projection neurons of the VTA are dopamine-producing neurons. dopamine codes for the difference between expected and actual
When the dopamine neurons of the VTA begin to fire in bursts, reward and thus constitutes a strong learning signal (see Box: The
large quantities of dopamine are released in the nucleus accumbens Dopamine Hypothesis of Addiction).
and the prefrontal cortex. Early animal studies pairing electrical Since each addictive drug has a specific molecular target that
stimulation of the VTA with operant responses (eg, lever press- engages distinct cellular mechanisms to activate the mesolimbic
ing) that result in strong reinforcement established the central role system, three classes can be distinguished: A first group binds to
of the mesolimbic dopamine system in reward processing. Direct Gio protein-coupled receptors, a second group interacts with
application of drugs into the VTA also acts as a strong reinforcer, ionotropic receptors or ion channels, and a third group tar-
and systemic administration of drugs of abuse causes release of dopa- gets the dopamine transporter (Table 32–1 and Figure 32–2).
mine. Even selective activation of dopamine neurons is sufficient to G protein-coupled receptors (GPCRs) of the Gio family inhibit
drive reinforcement and elicit adaptive behavioral changes typically neurons through postsynaptic hyperpolarization and presynaptic
observed with addictive drugs. These very selective interventions regulation of transmitter release. These three classes of drugs
use optogenetic methods. Blue light is delivered in a freely mov- loosely map onto three distinct cellular mechanisms to increase
ing mouse through light guides to activate channelrhodopsin, a dopamine levels. The first is a direct stimulation of the dopamine
light-gated cation channel that is artificially expressed in dopamine neurons (eg, nicotine). The second mechanism is the interference
neurons. As a result, mice will self-administer light to activate VTA with the reuptake of dopamine or the promotion of nonvesicular
dopamine neurons. After several pairings with a specific environ- release (eg, amphetamines). This happens in the target regions
ment, a long-lasting place preference is established. Once the light is as well as the VTA itself, because dopamine neurons also express
no longer available, a seeking behavior is observed. Finally some mice somatodendritic transporters, which normally clear dopamine
will self-stimulate even if they have to endure a punishment (light released by the dendrites. Although drugs of this class also affect
electric shock). Conversely, using inhibitory optogenetic effectors or transporters of other monoamines (norepinephrine, serotonin),
activation of inhibitory neurons upstream causes aversion. action on the dopamine transporter remains central for addiction.
This is consistent with the observations that antidepressants that
block serotonin and norepinephrine uptake, but not dopamine
uptake, do not cause addiction even after prolonged use. The third
mechanism is indirect, whereby the drugs inhibit γ-aminobutyric
mPFC
vHippo acid (GABA) neurons that act as local inhibitory interneurons
(eg, opioids).
D1 LHb

D2 VP
DEPENDENCE: TOLERANCE &
NAc RMTg WITHDRAWAL
LDT
With chronic exposure to addictive drugs, the brain shows signs
BLA VTA
of adaptation. For example, if morphine is used at short intervals,
the dose has to be progressively increased over the course of several
FIGURE 32–1 Major connections of the mesolimbic dopamine
system in the brain. Schematic diagram of the brain illustrating that
days to maintain rewarding or analgesic effects. This phenomenon
the dopamine projections (red) originate in the ventral tegmental is called tolerance. It may become a serious problem because of
area (VTA) and target the nucleus accumbens (NAc), prefrontal increasing side effects—eg, respiratory depression—that do not
cortex (mPFC), basolateral amygdala (BLA), and ventral pallidum show as much tolerance and may lead to fatalities associated with
(VP). Neurons in the NAc fall into two classes, one expressing type 1 overdose.
dopamine receptors (D1s) and the other expressing type 2 receptors Tolerance to opioids may be due to a reduction of the concen-
(D2s). Both classes contain GABAergic projection neurons (green); the tration of a drug or a shorter duration of action in a target system
D1R neurons send their axons to both the VP and the VTA (where they (pharmacokinetic tolerance). Alternatively, it may involve changes
target primarily the GABA interneurons), whereas the D2R neurons of µ-opioid receptor function (pharmacodynamic tolerance). In
send their axons selectively to the VP. The NAc is also a site of conver- fact, many µ-opioid receptor agonists promote strong receptor
gence of excitatory projections from the mPFC, the ventral hippocam-
phosphorylation that triggers the recruitment of the adaptor pro-
pus (vHippo), and the BLA. The midbrain dopamine neurons receive a
direct excitatory input (blue) from the lateral dorsal tegmentum (LDT),
tein β-arrestin, causing G proteins to uncouple from the receptor
while the GABA neurons of the rostromedial tegmentum (RMTg) at and to internalize within minutes (see Chapter 2). Since this
the tail of the VTA are excited by neurons from the lateral habenula decreases signaling, it is tempting to explain tolerance by such a
(LHb), typically when an aversive stimulus occurs. (Modified with permis- mechanism. However, morphine, which strongly induces toler-
sion from Lüscher C: Emergence of circuit model for addiction. Ann Rev Neurosci ance, does not recruit β-arrestins and fails to promote receptor
2016;39:257.) internalization (see Chapter 31). Conversely, other agonists that
 CHAPTER 32 Drugs of Abuse 577

TABLE 32–1 The mechanistic classification of drugs of abuse.1

Name Main Molecular Target Pharmacology Effect on Dopamine (DA) Neurons RR2

Drugs That Activate G Protein-Coupled Receptors

Opioids µ-OR (Gio) Agonist Disinhibition 4
Cannabinoids CB1R (Gio) Agonist Disinhibition 2
γ-Hydroxybutyric acid (GHB) GABABR (Gio) Weak agonist Disinhibition ?
LSD, mescaline, psilocybin 5-HT2AR (Gq) Partial agonist — 1
Drugs That Bind to Ionotropic Receptors and Ion Channels
Nicotine nAChR (α4β2) Agonist Excitation 4
Alcohol GABAAR, 5-HT3R, nAChR, NMDAR, Excitation, disinhibition (?) 3
Kir3 channels
Benzodiazepines GABAAR Positive modulator Disinhibition 3
Phencyclidine, ketamine NMDAR Antagonist — 1
Drugs That Bind to Transporters of Biogenic Amines
Cocaine DAT, SERT, NET Inhibitor Blocks DA uptake 5
Amphetamine DAT, NET, SERT, VMAT Reverses transport Blocks DA uptake, synaptic depletion 5
Ecstasy SERT > DAT, NET Reverses transport Blocks DA uptake, synaptic depletion ?
5-HTxR, serotonin receptor; CB1R, cannabinoid-1 receptor; DAT, dopamine transporter; GABA, γ-aminobutyric acid; Kir3 channels, G protein-coupled inwardly rectifying potas-
sium channels; LSD, lysergic acid diethylamide; µ-OR, µ-opioid receptor; nAChR, nicotinic acetylcholine receptor; NET, norepinephrine transporter; NMDAR, N-methyl-D-aspartate
receptor; R, receptor; SERT, serotonin transporter; VMAT, vesicular monoamine transporter; ? indicates data not available.
1
Drugs fall into one of three categories, targeting either G protein-coupled receptors, ionotropic receptors or ion channels, or biogenic amine transporters.
2
RR, relative risk of addiction; 1 = nonaddictive; 5 = highly addictive.

drive receptor internalization very efficiently induce only modest Adaptive changes become fully apparent once drug exposure
tolerance. Based on these observations, it has been hypothesized is terminated. This state is called withdrawal and is observed to
that desensitization and receptor internalization actually protect varying degrees after chronic exposure to most drugs of abuse.
the cell from overstimulation. In this model, morphine, by fail- Withdrawal from opioids in humans is particularly strong
ing to trigger receptor endocytosis, disproportionally stimulates (described below). Studies in rodents have added significantly to
adaptive processes, which eventually cause tolerance. Although our understanding of the neural and molecular mechanisms that
the molecular identity of these processes is still under investiga- underlie dependence. For example, signs of dependence, as well
tion, they may be similar to the ones involved in withdrawal as analgesia and reward, are abolished in knockout mice lack-
(see below). ing the µ-opioid receptor, but not in mice lacking other opioid

Ventral Tegmental Area Nucleus Accumbens

Class 1 From cortex

(opioids, THC, GHB):
Class 3
GPCRs
(cocaine, amphetamine,
ecstasy): transporters Glutamate

DA
GABA

GABA

Class 2
(benzodiazepines, Increased dopamine
nicotine, ethanol): (all addictive drugs)
channels

FIGURE 32–2 Neuropharmacologic classification of addictive drugs by primary target (see text and Table 32–1). DA, dopamine; GABA,
γ-aminobutyric acid; GHB, γ-hydroxybutyric acid; GPCRs, G protein-coupled receptors; THC, Δ9-tetrahydrocannabinol.
578 SECTION V Drugs That Act in the Central Nervous System

Animal Models in Addiction Research

Many of the recent advances in addiction research have been Subsequent exposures to the environment without the drug lead
made possible by the use of animal models. Since drugs of abuse to extinction of the place preference, which can be reinstated
are not only rewarding but also reinforcing, an animal will learn with a low dose of the drug or the presentation of a conditioned
a behavior (eg, press a lever) when paired with drug administra- stimulus. These persistent changes serve as a model of relapse
tion. In such a self-administration paradigm, the number of times and have been linked to synaptic plasticity of excitatory trans-
an animal is willing to press the lever in order to obtain a single mission in the ventral tegmental area, nucleus accumbens, and
dose reflects the strength of reinforcement and is therefore a prefrontal cortex (see also Box: The Dopamine Hypothesis of
measure of the rewarding properties of a drug. Observing with- Addiction). More sophisticated tests rely on self-administration
drawal signs specific for rodents (eg, escape jumps or “wet-dog” of the drug, in which a rat or a mouse has to press a lever in order
shakes after abrupt termination of chronic morphine administra- to obtain an injection of, for example, cocaine. Once the animal
tion) allows the quantification of dependence. Behavioral tests has learned the association with a conditioned stimulus (eg, light
for addiction in the rodent do not fully capture the complexity or brief sound), the simple presentation of the cue elicits drug
of the disease. However, it is possible to model core components seeking. Prolonged self-administration of addictive drugs over
of addiction; for example, by monitoring behavioral sensitization months leads to behaviors in rats that more closely resemble
and conditioned place preference. In the first test, an increase in human addiction. Such “addicted” rodents are very strongly
locomotor activity is observed with intermittent drug exposure. motivated to seek cocaine, continue looking for the drug even
The latter tests for the preference of a particular environment when no longer available, and self-administer cocaine despite
associated with drug exposure by measuring the time an animal negative consequences, such as punishment in the form of an
spends in the compartment where a drug was received com- electric foot shock. While there is little evidence for addicted
pared with the compartment where only saline was injected animals in the wild, these findings suggest that addiction is a
(conditioned place preference). Both tests have in common that disease that does not respect species boundaries once drugs
they are sensitive to cue-conditioned effects of addictive drugs. become available.

receptors (δ, κ). Although activation of the µ-opioid receptor The central problem is that even after successful withdrawal
initially strongly inhibits adenylyl cyclase, this inhibition becomes and prolonged drug-free periods, addicted individuals have a
weaker after several days of repeated exposure. The reduction of high risk of relapsing. Relapse is typically triggered by one of the
the inhibition of adenylyl cyclase is due to a counteradaptation of following three conditions: re-exposure to the addictive drug,
the enzyme system during exposure to the drug, which results in stress, or a context that recalls prior drug use. It appears that
overproduction of cAMP during subsequent withdrawal. Several when paired with drug use, a neutral stimulus may undergo a
mechanisms exist for this adenylyl cyclase compensatory response, switch and motivate (“trigger”) addiction-related behavior. This
including up-regulation of transcription of the enzyme. Increased phenomenon may involve synaptic plasticity in the target nuclei
cAMP concentrations in turn strongly activate the transcription of the mesolimbic projection (eg, projections from the medial
factor cyclic AMP response element binding protein (CREB), prefrontal cortex to the neurons of the nucleus accumbens that
leading to the regulation of downstream genes. Of the few such express the D1 receptors). Several recent studies suggest that the
genes identified to date, one of the most interesting is the gene recruitment of the dorsal striatum is responsible for the compul-
for the endogenous κ-opioid ligand dynorphin. The main targets sion. This switch may depend on synaptic plasticity in the nucleus
of dynorphin are the presynaptic κ-opioid receptors that regulate accumbens of the ventral striatum, where mesolimbic dopamine
the release of dopamine in the nucleus accumbens. More recently, afferents converge with glutamatergic afferents to modulate their
an input from the thalamus to the nucleus accumbens conveying function. If dopamine release codes for the prediction error
an aversive state during withdrawal has been implicated, further of reward (see Box: The Dopamine Hypothesis of Addiction),
elucidating the circuits underlying opioid dependence. pharmacologic stimulation of the mesolimbic dopamine system
will generate an unusually strong learning signal. Unlike natural
rewards, addictive drugs continue to increase dopamine even
ADDICTION: A DISEASE OF when reward is expected. Such overriding of the prediction error
MALADAPTIVE LEARNING signal may eventually be responsible for the usurping of memory
processes by addictive drugs.
Addiction is characterized by a high motivation to obtain and The involvement of learning and memory systems in addiction
use a drug despite negative consequences. With time, drug use is also suggested by clinical studies. For example, the role of con-
becomes compulsive (“wanting without liking”). Addiction is a text in relapse is supported by the report that soldiers who became
recalcitrant, chronic, and stubbornly relapsing disease that is very addicted to heroin during the Vietnam War had significantly bet-
difficult to treat. ter outcomes when treated after their return home, compared with
 CHAPTER 32 Drugs of Abuse 579

The Dopamine Hypothesis of Addiction

In the earliest version of the hypothesis described in this chapter, lose its rewarding properties. However, in DAT –/– mice, in which
mesolimbic dopamine was believed to be the neurochemical basal synaptic dopamine levels are high, cocaine still leads to
correlate of pleasure and reward. However, during the past increased dopamine release, presumably because other cocaine-
decade, experimental evidence has led to several revisions. Pha- sensitive monoamine transporters (NET, SERT) are able to clear
sic dopamine release may actually code for the prediction error some dopamine. When cocaine is given, these transporters are
of reward rather than the reward itself. This distinction is based also inhibited and dopamine is again increased. As a conse-
on pioneering observations in monkeys that dopamine neurons quence of this substitution among monoamine transporters,
in the ventral tegmental area (VTA) are most efficiently activated fluoxetine (a selective serotonin reuptake inhibitor, see Chapter
by a reward (eg, a few drops of fruit juice) that is not anticipated. 30) becomes addictive in DAT –/– mice. This concept is supported
When the animal learns to predict the occurrence of a reward by newer evidence showing that deletion of the cocaine-binding
(eg, by pairing it with a stimulus such as a sound), dopamine site on DAT leaves basal dopamine levels unchanged but abol-
neurons stop responding to the reward itself (juice), but increase ishes the rewarding effect of cocaine.
their firing rate when the conditioned stimulus (sound) occurs. The dopamine hypothesis of addiction has also been chal-
Finally, if reward is predicted but not delivered (sound but no lenged by the observation that salient stimuli that are not
juice), dopamine neurons are inhibited below their baseline rewarding (they may actually even be aversive and therefore nega-
activity and become silent. In other words, the mesolimbic tive reinforcers) also activate a subpopulation of dopamine neu-
system continuously scans the reward situation. It increases its rons in the VTA. The neurons that are activated by aversive stimuli
activity when reward is larger than expected and shuts down in preferentially project to the prefrontal cortex, while the dopamine
the opposite case, thus coding for the prediction error of reward. neurons inhibited by aversive stimuli are those that mostly tar-
Under physiologic conditions the mesolimbic dopamine get the nucleus accumbens. These recent findings suggest that
signal could represent a learning signal responsible for reinforc- in parallel to the reward system, a system for aversion-learning
ing constructive behavioral adaptation (eg, learning to press a originates in the VTA, which may be at the origin of the negative
lever for food). Addictive drugs, by directly increasing dopamine, affective state seen during drug withdrawal.
would generate a strong but inappropriate learning signal, thus Regardless of the many roles of dopamine under physi-
hijacking the reward system and leading to pathologic reinforce- ologic conditions, all addictive drugs significantly increase its
ment. As a consequence, behavior becomes compulsive; that is, concentration in target structures of the mesolimbic projection.
decisions are no longer planned and under control, but auto- This suggests that high levels of dopamine may actually be at
matic, which is the hallmark of addiction. the origin of the adaptive changes that underlie dependence
This appealing hypothesis has been challenged based on and addiction, a concept that is now supported by novel tech-
the observation that some reward and drug-related learning is niques that allow controlling the activity of dopamine neurons
still possible in the absence of dopamine. Another intriguing in vivo. In fact manipulations that drive sustained activity of
observation is that mice genetically modified to lack the primary VTA dopamine neurons cause the same cellular adaptations
molecular target of cocaine, the dopamine transporter DAT, and behavioral changes typically observed with addictive drug
still self-administer the drug. Only when transporters of other exposure, including late-stage symptoms such as persistence of
biogenic amines are also knocked out does cocaine completely self-stimulation during punishment.

addicts who remained in the environment where they had taken compulsively, or hypersexuality. Although large-scale studies are
the drug. In other words, cravings may recur at the presentation not yet available, an estimated one in seven parkinsonian patients
of contextual cues (eg, people, places, or drug paraphernalia). develops an addiction-like behavior when receiving dopamine
Current research therefore focuses on the effects of drugs on asso- agonists (see chapter 28).
ciative forms of synaptic plasticity, such as long-term potentiation Large individual differences exist also in vulnerability to
(LTP), which underlie learning and memory (see Box: Synaptic substance-related addiction. Whereas one person may become
Plasticity, Altered Circuit Function, & Addiction). “hooked” after a few doses, others may be able to use a drug occa-
Non-substance-dependent disorders, such as pathologic gam- sionally during their entire lives without ever having difficulty in
bling and compulsive shopping, share many clinical features stopping. Even when dependence is induced with chronic expo-
of addiction. Several lines of arguments suggest that they also sure, only a small percentage of dependent users progress to addic-
share the underlying neurobiologic mechanisms. This conclu- tion. For example, a retrospective analysis shows that after several
sion is supported by the clinical observation that, as an adverse decades of cocaine abuse, only 20% become addicted. With can-
effect of dopamine agonist medication, patients with Parkinson’s nabis, the fraction is only 10%. A similar percentage for cocaine
disease may become pathologic gamblers. Other patients may is also observed in rats and mice that have extended access to the
develop a habit for recreational activities, such as shopping, eating drug. Surprisingly, with dopamine neuron self-stimulation, the
580 SECTION V Drugs That Act in the Central Nervous System

Synaptic Plasticity, Altered Circuit Function, & Addiction

Long-term potentiation (LTP) is a form of experience- plasticity) and potentiates GABAA receptor-mediated inhibi-
dependent synaptic plasticity that is induced by activating tion of the GABA neurons in the VTA and the ventral pallidum
glutamate receptors of the N-methyl-D-aspartate (NMDA) type. (VP), both primary targets of the medium spiny neurons of the
Since NMDA receptors are blocked by magnesium at negative nucleus accumbens. As a consequence, the excitability of dopa-
potentials, their activation requires the concomitant release mine neurons is increased, the synaptic calcium sources altered,
of glutamate (presynaptic activity) onto a receiving neuron and the rules for subsequent LTP inverted. In the nucleus
that is depolarized (postsynaptic activity). Correlated pre- and accumbens, drug-evoked synaptic plasticity appears with some
postsynaptic activity durably enhances synaptic efficacy and delay and mostly involves the D1 receptor-expressing neurons,
triggers the formation of new connections. Because asso- which are the ones projecting back to the VTA to control the
ciativity is a critical component, LTP has become a leading activity of the GABA neurons as well as to the VP. Manipula-
candidate mechanism underlying learning and memory. LTP tions in mice that prevent or reverse drug-evoked plasticity in
can be elicited at glutamatergic synapses of the mesolimbic vivo also have effects on persistent changes of drug-associated
reward system and is modulated by dopamine. Drugs of abuse behavioral sensitization or cue-induced drug seeking, provid-
could therefore interfere with LTP at sites of convergence of ing more direct evidence for a causal role of synaptic plasticity
dopamine and glutamate projections (eg, ventral tegmental in drug-adaptive behavior. Together, a circuit model of staged
area [VTA], nucleus accumbens, or prefrontal cortex). Interest- drug-evoked synaptic plasticity is emerging, whereby various
ingly, exposure to an addictive drug triggers a specific form of symptoms are caused by changes in specific projections, even-
synaptic plasticity at excitatory afferents (drug-evoked synaptic tually combining into addiction.

fraction of mice that resist punishment is > 50%. Recent studies dissociative anesthetics (Table 32–1). Unlike addictive drugs,
in rats suggest that impulsivity or excessive anxiety may be crucial which primarily target the mesolimbic dopamine system, these
traits that represent a risk for addiction. The transition to addic- agents primarily target cortical and thalamic circuits. Lysergic
tion is determined by a combination of environmental and genetic acid diethylamide (LSD), for example, activates the serotonin
factors. Heritability of addiction, as determined by comparing 5-HT2A receptor in the prefrontal cortex, enhancing glutama-
monozygotic with dizygotic twins, is relatively modest for can- tergic transmission onto pyramidal neurons. These excitatory
nabinoids but very high for cocaine. It is of interest that the rela- afferents mainly come from the thalamus and carry sensory
tive risk for addiction (addiction liability) of a drug (Table 32–1) information of varied modalities, which may constitute a link
correlates with its heritability, suggesting that the neurobiologic to enhanced perception. Phencyclidine (PCP) and ketamine
basis of addiction common to all drugs is what is being inherited. produce a feeling of separation of mind and body (which is why
Further genomic analysis indicates that numerous, perhaps even they are called dissociative anesthetics) and, at higher doses,
hundreds of alleles need to function in combination to produce stupor and coma. The principal mechanism of action is a use-
the phenotype. However, identification of the genes involved dependent inhibition of glutamate receptors of the NMDA type.
remains elusive. Although some substance-specific candidate High doses of dextromethorphan, an over-the-counter cough
genes have been identified (eg, alcohol dehydrogenase, nicotinic suppressant, can also elicit a dissociative state. This effect is
acetylcholine receptor subunits), future research will also focus on mediated by a rather nonselective action on serotonin reuptake,
genes implicated in the neurobiologic mechanisms common to all and opioid, acetylcholine, and NMDA receptors.
addictive drugs. An appealing idea, now supported by experimen- The classification of NMDA antagonists as nonaddictive drugs
tal evidence, is the contribution of epigenetics as a determinant of was based on early assessments, which, in the case of PCP, have
addiction vulnerability. Cocaine regulates posttranslational modi- recently been questioned. In fact, animal research shows that PCP
fications of histones, DNA methylation, and signaling via non- can increase mesolimbic dopamine concentrations and has some
coding RNAs, which eventually may have an impact on behavior. reinforcing properties in rodents. Concurrent effects on both
The cellular mechanism involved and the relationship to synaptic thalamocortical and mesolimbic systems also exist for other addic-
plasticity are currently under investigation. tive drugs. Psychosis-like symptoms can be observed with can-
nabinoids, amphetamines, and cocaine, which may reflect their
effects on thalamocortical structures. For example, cannabinoids,
NONADDICTIVE DRUGS OF ABUSE in addition to their documented effects on the mesolimbic dopa-
mine system, also enhance excitation in cortical circuits through
Some drugs of abuse do not lead to addiction. This is the case presynaptic inhibition of GABA release.
for substances that alter perception without causing sensations Hallucinogens and NMDA antagonists, even if they do not
of reward and euphoria, such as the hallucinogens and the produce dependence or addiction, can still have long-term effects.
 CHAPTER 32 Drugs of Abuse 581

Flashbacks of altered perception can occur years after LSD use. tolerance and dependence. The withdrawal syndrome may be very
Moreover, chronic use of PCP may lead to an irreversible schizo- severe (except for codeine) and includes intense dysphoria, nausea
phrenia-like psychosis. or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis,
piloerection, sweating, diarrhea, yawning, and fever. Beyond the
withdrawal syndrome, which usually lasts no longer than a few
■ BASIC PHARMACOLOGY OF days, individuals who have received opioids as analgesics only
rarely develop addiction. In contrast, when taken for recreational
DRUGS OF ABUSE purposes, opioids are highly addictive. The relative risk of addic-
tion is 4 out of 5 on a scale of 1 (nonaddictive) to 5 (highly
Since all addictive drugs increase dopamine concentrations addictive).
in target structures of the mesolimbic projections, we classify
them on the basis of their molecular targets and the underlying
mechanisms (Table 32–1 and Figure 32–2). The first group Treatment
contains the opioids, cannabinoids, f-hydroxybutyric acid The opioid antagonist naloxone reverses the effects of a dose of
(GHB), and the hallucinogens, which all exert their action morphine or heroin within minutes. This may be life-saving in
through Gio protein-coupled receptors. The second group the case of a massive overdose (see Chapters 31 and 58). Naloxone
includes nicotine, alcohol, the benzodiazepines, dissocia- administration also provokes an acute withdrawal (precipitated
tive anesthetics, and some inhalants, which interact with abstinence) syndrome in a dependent person who has recently
ionotropic receptors or ion channels. The last group comprises taken an opioid.
cocaine, amphetamines, and ecstasy, which all bind to mono- In the treatment of opioid addiction, a long-acting opioid
amine transporters. The nonaddictive drugs are classified using (eg, methadone, buprenorphine, morphine sulphate) is often
the same criteria. substituted for the shorter-acting, more rewarding, opioid (eg,
heroin). For substitution therapy, methadone is given orally
DRUGS THAT ACTIVATE once daily, facilitating supervised intake. Using a partial agonist
(buprenorphine) and the much longer half-life (methadone,
GIO-COUPLED RECEPTORS morphine sulphate, and buprenorphine) may also have some
beneficial effects (eg, weaker drug sensitization, which typically
OPIOIDS requires intermittent exposures), but it is important to realize
Opioids may have been the first drugs to be abused (preceding that abrupt termination of methadone administration invari-
stimulants) and are still among the most commonly used for ably precipitates a withdrawal syndrome; that is, the subject
nonmedical purposes. on substitution therapy remains dependent. Levomethadone, a
preparation containing only the active enantiomer, has similar
kinetics and effects as methadone, but lower side effects, par-
Pharmacology & Clinical Aspects ticularly when cardiac repolarization is perturbed (long QT
As described in Chapter 31, opioids comprise a large family of interval in the electrocardiogram). Some countries (eg, Canada,
endogenous and exogenous agonists at three G protein-coupled Denmark, Netherlands, United Kingdom, Switzerland) even
receptors: the µ-, κ-, and δ-opioid receptors. Although all three allow substitution of medical heroin for street heroin. A follow-
receptors couple to inhibitory G proteins (ie, they all inhibit ade- up of a cohort of addicts who received heroin injections in a
nylyl cyclase), they have distinct, sometimes even opposing effects, controlled setting and had access to counseling indicates that
mainly because of the cell type-specific expression throughout addicts under heroin substitution have an improved health status
the brain. In the VTA, for example, µ-opioid receptors are selec- and are better integrated in society. Abuse of prescription opioids
tively expressed on GABA neurons (which they inhibit), whereas has soared in the USA over the last 10 years, and the National
κ-opioid receptors are expressed on and inhibit dopamine neu- Institute on Drug Abuse (NIDA) estimates that more than
rons. This may explain why µ-opioid agonists cause euphoria, 2 million individuals are dependent on these substances, some
whereas κ agonists induce dysphoria. of whom may become heroin addicts.
In line with the latter observations, the rewarding effects of
morphine are absent in knockout mice lacking µ receptors but
persist when either of the other opioid receptors are ablated. In CANNABINOIDS
the VTA, µ opioids cause an inhibition of GABAergic inhibitory
interneurons, which leads eventually to a disinhibition of dopa- Endogenous cannabinoids that act as neurotransmitters include
mine neurons. 2-arachidonyl glycerol (2-AG) and anandamide, both of which
The most commonly abused µ opioids include morphine, bind to CB1 receptors. These very lipid-soluble compounds are
heroin (diacetylmorphine, which is rapidly metabolized to mor- released at the postsynaptic somatodendritic membrane, and dif-
phine), codeine, and oxycodone. Meperidine abuse is common fuse through the extracellular space to bind at presynaptic CB1
among health professionals. All of these drugs induce strong receptors, where they inhibit the release of either glutamate or
582 SECTION V Drugs That Act in the Central Nervous System

GABA. Because of such backward signaling, endocannabinoids binding sites. The protein that contains a high-affinity binding
are called retrograde messengers. In the hippocampus, release site (1 µM) for GHB has been cloned, but its involvement in the
of endocannabinoids from pyramidal neurons selectively affects cellular effects of GHB at pharmacologic concentrations remains
inhibitory transmission and may contribute to the induction of unclear. The low-affinity binding site (1 mM) has been identified
synaptic plasticity during learning and memory formation. as the GABAB receptor. In mice that lack GABAB receptors, even
Exogenous cannabinoids, eg, in marijuana, which when smoked very high doses of GHB have no effect; this suggests that GABAB
contains thousands of organic and inorganic chemical compounds, receptors are the sole mediators of GHB’s pharmacologic action.
exert their pharmacologic effects through active substances includ- GHB was first synthesized in 1960 and introduced as a general
ing ∆9-tetra-hydrocannabinol (THC), a powerful psychoactive anesthetic. Because of its narrow safety margin and its addictive
substance. Like opioids, THC causes disinhibition of dopamine potential, it is not available in the USA for this purpose. Sodium
neurons, mainly by presynaptic inhibition of GABA neurons in the oxybate can, however, be prescribed (under restricted access rules)
VTA. The half-life of THC is about 4 hours. The onset of effects of to treat narcolepsy, because GHB decreases daytime sleepiness
THC after smoking marijuana occurs within minutes and reaches a and episodes of cataplexy through a mechanism unrelated to the
maximum after 1–2 hours. The most prominent effects are eupho- reward system. Before causing sedation and coma, GHB causes
ria and relaxation. Users also report feelings of well-being, grandi- euphoria, enhanced sensory perceptions, a feeling of social close-
osity, and altered perception of passage of time. Dose-dependent ness, and amnesia. These properties have made it a popular “club
perceptual changes (eg, visual distortions), drowsiness, diminished drug” that goes by colorful street names such as “liquid ecstasy,”
coordination, and memory impairment may occur. Cannabinoids “grievous bodily harm,” or “date rape drug.” As the latter name
can also create a dysphoric state and, in rare cases following the use suggests, GHB has been used in date rapes because it is odorless
of very high doses, eg, in hashish, result in visual hallucinations, and can be readily dissolved in beverages. It is rapidly absorbed
depersonalization, and frank psychotic episodes. Additional effects after ingestion and reaches a maximal plasma concentration
of THC, eg, increased appetite, attenuation of nausea, decreased 20–30 minutes after ingestion of a 10–20 mg/kg dose. The elimi-
intraocular pressure, and relief of chronic pain, have led to the nation half-life is about 30 minutes.
use of cannabinoids in medical therapeutics. The justification of Although GABAB receptors are expressed on all neurons of the
medicinal use of marijuana was comprehensively examined by the VTA, GABA neurons are much more sensitive to GHB than are
Institute of Medicine (IOM) of the National Academy of Sciences dopamine neurons (Figure 32–3). This is reflected by the EC50s,
in its 1999 report, Marijuana & Medicine. Today, medical use of which differ by about one order of magnitude, and indicates the dif-
botanical marijuana has been legalized in 25 states and the District ference in coupling efficiency of the GABAB receptor and the potas-
of Columbia. Nevertheless this continues to be a controversial issue, sium channels responsible for the hyperpolarization. Because GHB
mainly because of the fear that cannabinoids may serve as a gateway is a weak agonist, only GABA neurons are inhibited at the concen-
to the consumption of “hard” drugs or cause schizophrenia in indi- trations typically obtained with recreational use. This feature may
viduals with a predisposition. underlie the reinforcing effects of GHB and the basis for addiction
Chronic exposure to marijuana leads to dependence, which to the drug. At higher doses, however, GHB also hyperpolarizes
is revealed by a distinctive, but mild and short-lived, withdrawal dopamine neurons, eventually completely inhibiting dopamine
syndrome that includes restlessness, irritability, mild agitation, release. Such an inhibition of the VTA may in turn preclude its
insomnia, nausea, and cramping. The relative risk for addiction is 2. activation by other addictive drugs and may explain why GHB
The synthetic ∆9-THC analog dronabinol is a US Food might have some usefulness as an “anticraving” compound.
and Drug Administration (FDA) -approved cannabinoid agonist
currently marketed in the USA and some European countries.
Nabilone, an older commercial ∆9-THC analog, was recently LSD, MESCALINE, & PSILOCYBIN
reintroduced in the USA for treatment of chemotherapy-induced
emesis. Nabiximols is a botanical drug obtained by standard extrac- LSD, mescaline, and psilocybin are commonly called hallucino-
tion. Its active principles are ∆9-THC and cannabidiol. Initially gens because of their ability to alter consciousness such that the
only marketed in the United Kingdom, it is now widely available to individual senses things that are not present. They induce, often in
treat symptoms of multiple sclerosis. In the USA, nabiximols is in an unpredictable way, perceptual symptoms, including shape and
phase III testing for cancer pain. The cannabinoid system is likely color distortion. Psychosis-like manifestations (depersonalization,
to emerge as an important drug target in the future because of its hallucinations, distorted time perception) have led some to clas-
apparent involvement in several therapeutically desirable effects. sify these drugs as psychotomimetics. They also produce somatic
symptoms (dizziness, nausea, paresthesias, and blurred vision).
Some users have reported intense reexperiencing of perceptual
GAMMA-HYDROXYBUTYRIC ACID effects (flashbacks) up to several years after the last drug exposure.
Hallucinogens differ from most other drugs described in this
Gamma-hydroxybutyric acid (GHB, or sodium oxybate for its chapter in that they induce neither dependence nor addiction.
salt form) is produced during the metabolism of GABA, but the However, repetitive exposure still leads to rapid tolerance (also
function of this endogenous agent is unknown at present. The called tachyphylaxis). Animals do not self-administer hallucino-
pharmacology of GHB is complex because there are two distinct gens, suggesting that they are not rewarding to them. Additional
 CHAPTER 32 Drugs of Abuse 583

Opioids

MOR

GABA

Ca2+ K+
DA VGCC
Kir3
MOR
MOR
GABA Ca2+ βγ βγ

THC

CB1R

GABA
DA GABAAR

GHB

GABA B
DA

GABA

FIGURE 32–3 Disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA) through drugs that act via Gio-coupled receptors.
Top: Opioids target µ-opioid receptors (MORs) that in the VTA are located exclusively on γ-aminobutyric acid (GABA) neurons. MORs are expressed
on the presynaptic terminal of these cells and the somatodendritic compartment of the postsynaptic cells. Each compartment has distinct effectors
(insets). G protein-βγ-mediated inhibition of voltage-gated calcium channels (VGCC) is the major mechanism in the presynaptic terminal. Conversely,
in dendrites MORs activate K channels. Together the pre- and postsynaptic mechanisms reduce transmitter release and suppress activity, ultimately
taking away the inhibition by the GABA neurons. Middle: Δ9-tetrahydrocannabinol (THC) and other cannabinoids mainly act through presynaptic inhi-
bition. Bottom: Gamma-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are more
sensitive to GHB than are DA neurons, leading to disinhibition at concentrations typically obtained with recreational use. CB1R, cannabinoid receptors.

studies show that these drugs also fail to stimulate dopamine Gq type and generates inositol trisphosphate (IP3), leading to a
release, further supporting the idea that only drugs that activate release of intracellular calcium. Although hallucinogens, and LSD
the mesolimbic dopamine system are addictive. Instead, hal- in particular, have been proposed for several therapeutic indica-
lucinogens increase glutamate release in the cortex, presumably tions, efficacy has never been demonstrated.
by enhancing excitatory afferent input via presynaptic serotonin
receptors (eg, 5-HT2A) from the thalamus.
LSD is an ergot alkaloid. After synthesis, blotter paper or sugar DRUGS THAT MEDIATE THEIR
cubes are sprinkled with the liquid and allowed to dry. When LSD EFFECTS VIA IONOTROPIC
is swallowed, psychoactive effects typically appear after 30 minutes
and last 6–12 hours. During this time, subjects have impaired
RECEPTORS
ability to make rational judgments and understand common NICOTINE
dangers, which puts them at risk for accidents and personal injury.
In an adult, a typical dose is 20–30 mcg. LSD is not con- In terms of numbers affected, addiction to nicotine exceeds all
sidered neurotoxic, but like most ergot alkaloids, it may lead to other forms of addiction, affecting more than 50% of all adults
strong contractions of the uterus that can induce abortion (see in some countries. Nicotine exposure occurs primarily through
Chapter 16). smoking of tobacco, which causes associated diseases that are
The main molecular target of LSD and other hallucinogens is responsible for many preventable deaths. The chronic use of chew-
the 5-HT2A receptor. This receptor couples to G proteins of the ing tobacco and snuff tobacco is also addictive.
584 SECTION V Drugs That Act in the Central Nervous System

Nicotine is a selective agonist of the nicotinic acetylcholine benzodiazepines for their euphoriant effects, but most often abuse
receptor (nAChR) that is normally activated by acetylcholine (see occurs concomitant with other drugs, eg, to attenuate anxiety dur-
Chapters 6 and 7). Based on nicotine’s enhancement of cognitive ing withdrawal from opioids.
performance and the association of Alzheimer’s dementia with a Benzodiazepine dependence is very common, and diagnosis of
loss of ACh-releasing neurons from the nucleus basalis of Meynert, addiction is probably often missed. Withdrawal from benzodiaz-
nAChRs are believed to play an important role in many cognitive epines occurs within days of stopping the medication and varies
processes. The rewarding effect of nicotine requires involvement of as a function of the half-life of elimination. Symptoms include
the VTA, in which nAChRs are expressed on dopamine neurons. irritability, insomnia, phonophobia and photophobia, depression,
When nicotine excites projection neurons, dopamine is released in muscle cramps, and even seizures. Typically, these symptoms taper
the nucleus accumbens and the prefrontal cortex, thus fulfilling the off within 1–2 weeks.
dopamine requirement of addictive drugs. Recent work has identi- Benzodiazepines are positive modulators of the GABAA recep-
fied α4β2-containing channels in the VTA as the nAChRs that tor, increasing both single-channel conductance and open-channel
are required for the rewarding effects of nicotine. This statement is probability. GABAA receptors are pentameric structures consisting
based on the observation that knockout mice deficient for the β2 of α, β, and γ subunits (see Chapter 22). GABA receptors on
subunit lose interest in self-administering nicotine, and that in these dopamine neurons of the VTA lack α1, a subunit isoform that
mice, this behavior can be restored through an in vivo transfec- is present in GABA neurons nearby (ie, interneurons). Because
tion of the β2 subunit in neurons of the VTA. Electrophysiologic of this difference, unitary synaptic currents in interneurons are
evidence suggests that homomeric nAChRs made exclusively of α7 larger than those in dopamine neurons, and when this difference
subunits also contribute to the reinforcing effects of nicotine. These is amplified by benzodiazepines, interneurons fall silent. GABA is
receptors are mainly expressed on synaptic terminals of excitatory no longer released, and benzodiazepines lose their effect on dopa-
afferents projecting onto the dopamine neurons. They also contrib- mine neurons, ultimately leading to disinhibition of the dopamine
ute to nicotine-evoked dopamine release and the long-term changes neurons. The rewarding effects of benzodiazepines are, therefore,
induced by the drugs related to addiction (eg, long-term synaptic mediated by α1-containing GABAA receptors expressed on VTA
potentiation of excitatory inputs). neurons. Receptors containing α5 subunits seem to be required
Nicotine withdrawal is mild compared with opioid withdrawal for tolerance to the sedative effects of benzodiazepines, and studies
and involves irritability and sleep problems. However, nicotine is in humans link α2β3-containing receptors to alcohol dependence
among the most addictive drugs (relative risk 4), and relapse after (the GABAA receptor is also a target of alcohol, see following text).
attempted cessation is very common. Taken together, a picture is emerging linking GABAA receptors
that contain the α1 subunit isoform to their addiction liability.
Treatment By extension, α1-sparing compounds, which at present remain
experimental and are not approved for human use, may eventually
Treatments for nicotine addiction include nicotine itself in forms that be preferred to treat anxiety disorders because of their reduced risk
are slowly absorbed and several other drugs. Nicotine that is chewed, of induced addiction.
inhaled, or transdermally delivered can be substituted for the nicotine Barbiturates, which preceded benzodiazepines as the most
in cigarettes, thus slowing the pharmacokinetics and eliminating the commonly abused sedative-hypnotics (after ethanol), are now
many complications associated with the toxic substances found in rarely prescribed to outpatients and therefore constitute a less
tobacco smoke. Recently, two partial agonists of α4β2-containing common prescription drug problem than they did in the past.
nAChRs have been characterized: the plant-extract cytisine and its Street sales of barbiturates, however, continue. Management
synthetic derivative varenicline. Both work by occupying nAChRs of barbiturate withdrawal and addiction is similar to that of
on dopamine neurons of the VTA, thus preventing nicotine from benzodiazepines.
exerting its action. Varenicline may impair the capacity to drive and
has been associated with suicidal ideation. The antidepressant bupro-
pion is approved for nicotine cessation therapy. It is most effective ALCOHOL
when combined with behavioral therapies.
Many countries have banned smoking in public places to create Alcohol (ethanol, see Chapter 23) is regularly used by a majority
smoke-free environments. This important step not only reduces of the population in many Western countries. Although only a
passive smoking and the hazards of secondhand smoke, but also minority becomes dependent and addicted, abuse is a very seri-
the risk that ex-smokers will be exposed to smoke, which as a ous public health problem because of the social costs and many
contextual cue, may trigger relapse. diseases associated with alcoholism.

BENZODIAZEPINES Pharmacology
The pharmacology of alcohol is complex, and no single receptor
Benzodiazepines are commonly prescribed as anxiolytics and sleep mediates all of its effects. On the contrary, alcohol alters the func-
medications. They represent a definite risk for abuse, which has tion of several receptors and cellular functions, including GABAA
to be weighed against their beneficial effects. Some persons abuse receptors, Kir3/GIRK channels, adenosine reuptake (through
 CHAPTER 32 Drugs of Abuse 585

the equilibrative nucleoside transporter, ENT1), glycine recep- experiences have been reported. Although ketamine and phency-
tor, NMDA receptor, and 5-HT3 receptor. They are all, with the clidine do not cause dependence and addiction (relative risk = 1),
exception of ENT1, either ionotropic receptors or ion channels. It chronic exposure, particularly to PCP, may lead to long-lasting
is not clear which of these targets is responsible for the increase of psychosis closely resembling schizophrenia, which may persist
dopamine release from the mesolimbic reward system. The inhibi- beyond drug exposure. Surprisingly, intravenous administration
tion of ENT1 is probably not responsible for the rewarding effects of ketamine can eliminate episodes of depression within hours
(ENT1 knockout mice drink more than controls) but seems to (see Chapter 30), which is in strong contrast to selective serotonin
be involved in alcohol dependence through an accumulation of reuptake inhibitors and other antidepressants, which usually take
adenosine, stimulation of adenosine A2 receptors, and ensuing weeks to act. The antidepressive mechanism is believed to involve
enhanced CREB signaling. the antagonism of NMDA receptors, thus favoring the mTOR
Dependence becomes apparent 6–12 hours after cessation pathway downstream of other glutamate receptors. Recent evi-
of heavy drinking as a withdrawal syndrome that may include dence suggests an alternate explanation. Hydroxynorketamine, a
tremor (mainly of the hands), nausea and vomiting, exces- metabolite of ketamine, may actually target AMPA receptors to
sive sweating, agitation, and anxiety. In some individuals, exert the antidepressant effect. Regardless, a limitation is the tran-
this is followed by visual, tactile, and auditory hallucinations sient nature of the effect, which wears off within days even with
12–24 hours after cessation. Generalized seizures may manifest repetitive administration.
after 24–48 hours. Finally, 48–72 hours after cessation, an
alcohol withdrawal delirium (delirium tremens) may become
apparent in which the person hallucinates, is disoriented, and INHALANTS
shows evidence of autonomic instability. Delirium tremens is
Inhalant abuse is defined as recreational exposure to chemical
associated with 5–15% mortality.
vapors, such as nitrites, ketones, and aliphatic and aromatic
hydrocarbons. These substances are present in a variety of
Treatment household and industrial products that are inhaled by “sniffing,”
Treatment of ethanol withdrawal is supportive and relies on “huffing,” or “bagging.” Sniffing refers to inhalation from an open
benzodiazepines, taking care to use compounds such as oxazepam container, huffing to the soaking of a cloth in the volatile sub-
and lorazepam, which are not as dependent on oxidative hepatic stance before inhalation, and bagging to breathing in and out of a
metabolism as most other benzodiazepines. In patients in whom paper or plastic bag filled with fumes. It is common for novices to
monitoring is not reliable and liver function is adequate, a longer- start with sniffing and progress to huffing and bagging as addic-
acting benzodiazepine such as chlordiazepoxide is preferred. tion develops. Inhalant abuse is particularly prevalent in children
As in the treatment of all chronic drug abuse problems, heavy and young adults.
reliance is placed on psychosocial approaches to alcohol addiction. The exact mechanism of action of most volatile substances
This is perhaps even more important for the alcoholic patient remains unknown. Altered function of ionotropic receptors and
because of the ubiquitous presence of alcohol in many social ion channels throughout the central nervous system has been
contexts. demonstrated for a few. Nitrous oxide, for example, binds to
The pharmacologic treatment of alcohol addiction is limited, NMDA receptors, and fuel additives enhance GABAA receptor
although several compounds, with different goals, have been used. function. Most inhalants produce euphoria; increased excitability
Therapy is discussed in Chapter 23. of the VTA has been documented for toluene and may underlie its
addiction risk. Other substances, such as amyl nitrite (“poppers”),
primarily produce smooth muscle relaxation and enhance erec-
KETAMINE & PHENCYCLIDINE (PCP) tion but are not addictive. With chronic exposure to the aromatic
hydrocarbons (eg, benzene, toluene), toxic effects can be observed
Ketamine and PCP were developed as general anesthetics (see in many organs, including white matter lesions in the central ner-
Chapter 25), but only ketamine is still used for this applica- vous system. Management of overdose remains supportive.
tion. Both drugs, along with others, are now classified as “club
drugs” and sold under names such as “angel dust,” “Hog,” and
“Special K.” They owe their effects to their use-dependent, non- DRUGS THAT BIND TO
competitive antagonism of the NMDA receptor. The effects of
these substances became apparent when patients undergoing
TRANSPORTERS OF BIOGENIC
surgery reported unpleasant vivid dreams and hallucinations after AMINES
anesthesia. Ketamine and PCP are white crystalline powders in
their pure forms, but on the street they are also sold as liquids, Cocaine
capsules, or pills, which can be snorted, ingested, injected, or The prevalence of cocaine abuse has increased greatly over the last
smoked. Psychedelic effects last for about 1 hour and also include decade and now represents a major public health problem world-
increased blood pressure, impaired memory function, and visual wide. Cocaine is highly addictive (relative risk = 5), and its use is
alterations. At high doses, unpleasant out-of-body and near-death associated with a number of complications.
586 SECTION V Drugs That Act in the Central Nervous System

Cocaine is an alkaloid found in the leaves of Erythroxylum of the newborn, and the mothers faced harsh legal consequences.
coca, a shrub indigenous to the Andes. For more than 100 years, The follow-up of the children, now adults, does not confirm a
it has been extracted and used in clinical medicine, mainly as a drug-specific handicap in cognitive performance. Moreover, in
local anesthetic and to dilate pupils in ophthalmology. Sigmund this population, the percentage of drug-users is comparable to
Freud famously proposed its use to treat depression and alcohol controls matched for socioeconomic environment.
dependence, but addiction quickly brought an end to this idea. Susceptible individuals may become dependent and addicted
Cocaine hydrochloride is a water-soluble salt that can be after only a few exposures to cocaine. Although a withdrawal
injected or absorbed by any mucosal membrane (eg, nasal snort- syndrome is reported, it is not as strong as that observed with
ing). When heated in an alkaline solution, it is transformed into opioids. Tolerance may develop, but in some users, a reverse
the free base, “crack cocaine,” which can then be smoked. Inhaled tolerance is observed; that is, they become sensitized to small
crack cocaine is rapidly absorbed in the lungs and penetrates doses of cocaine. This behavioral sensitization is in part context-
swiftly into the brain, producing an almost instantaneous “rush.” dependent. Cravings are very strong and underlie the very high
In the peripheral nervous system, cocaine inhibits voltage- addiction liability of cocaine. To date, no specific antagonist is
gated sodium channels, thus blocking initiation and conduction available, and the management of intoxication remains support-
of action potentials (see Chapter 26). This mechanism, underlying ive. Developing a pharmacologic treatment for cocaine addiction
its effect as a local anesthetic, seems responsible for neither the is a top priority.
acute rewarding nor the addictive effects. In the central nervous
system, cocaine blocks the uptake of dopamine, noradrenaline,
and serotonin through their respective transporters. The block AMPHETAMINES
of the dopamine transporter (DAT), by increasing dopamine
concentrations in the nucleus accumbens, has been implicated Amphetamines are a group of synthetic, indirect-acting sympa-
in the rewarding effects of cocaine (Figure 32–4). In fact, the thomimetic drugs that cause the release of endogenous biogenic
rewarding effects of cocaine are abolished in mutant mice with a amines, such as dopamine and noradrenaline (see Chapters 6 and 9).
cocaine-insensitive DAT. The activation of the sympathetic ner- Amphetamine, methamphetamine, and their many derivatives
vous system results mainly from blockage of the norepinephrine exert their effects by reversing the action of biogenic amine trans-
transporter (NET) and leads to an acute increase in arterial pres- porters at the plasma membrane. Amphetamines are substrates of
sure, tachycardia, and often, ventricular arrhythmias. Users typi- these transporters and are taken up into the cell (Figure 32–4).
cally lose their appetite, are hyperactive, and sleep little. Cocaine Once in the cell, amphetamines interfere with the vesicular
exposure increases the risk for intracranial hemorrhage, ischemic monoamine transporter (VMAT; see Figure 6–4), depleting syn-
stroke, myocardial infarction, and seizures. Cocaine overdose aptic vesicles of their neurotransmitter content. As a consequence,
may lead to hyperthermia, coma, and death. In the 1970s, when levels of dopamine (or other transmitter amine) in the cytoplasm
crack-cocaine appeared in the USA, it was suggested that the drug increase and quickly become sufficient to cause release into the
is particularly harmful to the fetus in addicted pregnant women. synapse by reversal of the plasma membrane DAT. Normal vesicu-
The term “crack-baby” was used to describe a specific syndrome lar release of dopamine consequently decreases (because synaptic

Cocaine Amphetamine

VMAT

Amph
DA

DAT
DAT
DAT
DA DA DA
DA
Cocaine Amph

FIGURE 32–4 Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left: Cocaine inhibits
the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration.
Right: Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine
interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are
depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further
increasing extracellular DA concentrations.
 CHAPTER 32 Drugs of Abuse 587

vesicles contain less transmitter), whereas nonvesicular release is a marked intracellular depletion for 24 hours after a single dose.
increases. Similar mechanisms apply for other biogenic amines With repetitive administration, serotonin depletion may become
(serotonin and norepinephrine). permanent, which has triggered a debate on its neurotoxicity.
Together with GHB and ecstasy, amphetamines are often Although direct proof from animal models for neurotoxicity
referred to as “club drugs” because they are increasingly popular remains weak, several studies report long-term cognitive impair-
in the club scene. They are often produced in small clandestine ment in heavy users of MDMA.
laboratories, which makes their precise chemical identification In contrast, there is a wide consensus that MDMA has several
difficult. They differ from ecstasy chiefly in the context of use: acute toxic effects, in particular hyperthermia, which along with
intravenous administration and “hard-core” addiction are far dehydration (eg, caused by an all-night dance party) may be fatal.
more common with amphetamines, especially methamphetamine. Other complications include serotonin syndrome (mental status
In general, amphetamines lead to elevated catecholamine levels change, autonomic hyperactivity, and neuromuscular abnormali-
that increase arousal and reduce sleep, whereas the effects on the ties; see Chapter 16) and seizures. Following warnings about the
dopamine system mediate euphoria but may also cause abnor- dangers of MDMA, some users have attempted to compensate
mal movements and precipitate psychotic episodes. Effects on for hyperthermia by drinking excessive amounts of water, causing
serotonin transmission may play a role in the hallucinogenic and water intoxication involving severe hyponatremia, seizures, and
anorexigenic functions as well as in the hyperthermia often caused even death.
by amphetamines. Withdrawal is marked by a mood “offset” characterized by
Unlike many other abused drugs, amphetamines are neu- depression lasting up to several weeks. There have also been
rotoxic. The exact mechanism is not known, but neurotoxicity reports of increased aggression during periods of abstinence in
depends on the NMDA receptor and affects mainly serotonin and chronic MDMA users.
dopamine neurons. Taken together, the evidence for irreversible damage to the
Amphetamines are typically taken initially in pill form by brain, although not completely convincing, implies that even
abusers, but can also be smoked or injected. Heavy users often occasional recreational use of MDMA cannot be considered safe.
progress rapidly to intravenous administration. Within hours after
oral ingestion, amphetamines increase alertness and cause eupho-
ria, agitation, and confusion. Bruxism (tooth grinding) and skin
flushing may occur. Effects on heart rate may be minimal with ■ CLINICAL PHARMACOLOGY OF
some compounds (eg, methamphetamine), but with increasing DEPENDENCE & ADDICTION
dosage these agents often lead to tachycardia and dysrhythmias.
Hypertensive crisis and vasoconstriction may lead to stroke. To date no single pharmacologic treatment (even in combination
Spread of HIV and hepatitis infection in inner cities has been with behavioral interventions) efficiently eliminates addiction.
closely associated with needle sharing by intravenous users of This is not to say that addiction is irreversible. Pharmacologic
methamphetamine. interventions may in fact be useful at all stages of the disease. This
With chronic use, amphetamine tolerance may develop, lead- is particularly true in the case of a massive overdose, in which
ing to dose escalation. Withdrawal consists of dysphoria, drowsi- reversal of drug action may be a life-saving measure. However,
ness (in some cases, insomnia), and general irritability. FDA-approved antagonists are available only for opioids and
benzodiazepines.
Pharmacologic interventions may also aim to alleviate the
ECSTASY (MDMA) withdrawal syndrome, particularly after opioid exposure. On the
assumption that withdrawal reflects—at least in part—a hyperac-
Ecstasy is the name of a class of drugs that includes a large variety tivity of central adrenergic systems, the α2-adrenoceptor agonist
of derivatives of the amphetamine-related compound methylene- clonidine (also used as a centrally active antihypertensive drug, see
dioxymethamphetamine (MDMA). MDMA was originally used Chapter 11) has been used with some success to attenuate with-
in some forms of psychotherapy, but no medically useful effects drawal. Today, most clinicians prefer to manage opioid withdrawal
were documented. This is perhaps not surprising, because the by very slowly tapering the administration of long-acting opioids.
main effect of ecstasy appears to be to foster feelings of intimacy Another widely accepted treatment is substitution of a legally
and empathy without impairing intellectual capacities. Today, available agonist that acts at the same receptor as the abused
MDMA and its many derivatives are often produced in small drug. This approach has been approved for opioids and nicotine.
quantities in ad hoc laboratories and distributed at parties or For example, heroin addicts may receive methadone to replace
“raves,” where it is taken orally. Ecstasy therefore is the prototypic heroin; smoking addicts may receive nicotine continuously via a
designer drug and, as such, is increasingly popular. transdermal patch system to replace smoking. In general, a rapid-
Similar to the amphetamines, MDMA causes release of bio- acting substance is replaced with one that acts or is absorbed
genic amines by reversing the action of their respective transport- more slowly. Substitution treatments are largely justified by the
ers. It has a preferential affinity for the serotonin transporter benefits of reducing associated health risks, the reduction of drug-
(SERT) and therefore most strongly increases the extracellular associated crime, and better social integration. Although depen-
concentration of serotonin. This release is so profound that there dence persists, it may be possible, with the support of behavioral
588 SECTION V Drugs That Act in the Central Nervous System

interventions, to motivate drug users to gradually reduce the dose a substantial risk of suicide—this drug is no longer used clini-
and become abstinent. cally. It was initially used in conjunction with diet and exercise
The biggest challenge is the treatment of addiction itself. Sev- for patients with a body mass index above 30 kg/m2 (27 kg/m2
eral approaches have been proposed, but all remain experimental. if associated risk factors, such as type 2 diabetes or dyslipidemia,
One approach is to pharmacologically reduce cravings. The are present). Although a recent large-scale study confirmed that
µ-opioid receptor antagonist and partial agonist naltrexone is rimonabant is effective for smoking cessation and the prevention
FDA-approved for this indication in opioid and alcohol addiction. of weight gain in smokers who quit, this indication has never been
Its effect is modest and may involve a modulation of endogenous approved. While the cellular mechanism of rimonabant remains
opioid systems. to be elucidated, data in rodents convincingly demonstrate that
Clinical trials are currently being conducted with a number this compound can reduce self-administration in naive as well as
of drugs, including the high-affinity GABAB-receptor agonist drug-experienced animals.
baclofen, and initial results have shown a significant reduction While still experimental, the emergence of a circuit model
of craving. This effect may be mediated by the inhibition of the for addiction has prompted interest in neuromodulatory inter-
dopamine neurons of the VTA, which is possible at baclofen ventions, such as deep brain stimulation (DBS) or transcranial
concentrations obtained by oral administration because of its very magnetic stimulation (TMS). Inspired by optogenetic “treat-
high affinity for the GABAB receptor. ments” in rodent models of addiction, novel protocols have
Rimonabant is an inverse agonist of the CB1 receptor that been proposed for DBS in the nucleus accumbens or TMS
behaves like an antagonist of cannabinoids. It was developed of the prefrontal cortex. Case studies seem to confirm the
for smoking cessation and to facilitate weight loss. Because of potential of such approaches, but controlled clinical studies
frequent adverse effects—most notably severe depression carrying are lacking.

SUMMARY Drugs Used to Treat Dependence and Addiction

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Application Interactions

OPIOID RECEPTOR ANTAGONIST

• Naloxone Nonselective antagonist of Reverses the acute effects of Opioid overdose Effect much shorter than morphine
opioid receptors opioids; can precipitate (1–2 h); therefore several injections
severe abstinence syndrome required

• Naltrexone Antagonist of opioid Blocks effects of illicit Treatment of alcoholism, Half-life 10 h (oral); 5–10 days
receptors opioids opioid addiction (depot injection)

SYNTHETIC OPIOID
• Methadone Slow-acting agonist of Acute effects similar to Substitution therapy for High oral bioavailability • half-life highly
µ-opioid receptor morphine (see text) opioid addicts variable among individuals (range
4–130 h) • Toxicity: Respiratory
depression, constipation, miosis,
tolerance, dependence, arrhythmia, and
withdrawal symptoms

• Levomethadone “Enantiopure” methadone Similar to morphine and Substitution therapy Less toxic compared to racemic
containing only the left- methadone, but at half the methadone, particularly related to
enantiomer of the molecule dose of the latter cardiac adverse effects (long QT interval)

• Morphine A salt containing morphine Slow-release version with a Substitution therapy

sulphate sulfate pentahydrate longer action than morphine

PARTIAL l-OPIOID RECEPTOR AGONIST

• Buprenorphine Partial agonist at µ-opioid Attenuates acute effects of Oral substitution therapy for Long half-life (40 h) • formulated
receptors morphine opioid addicts together with naloxone to avoid illicit IV
injections

NICOTINIC RECEPTOR PARTIAL AGONIST

• Varenicline Partial agonist of nicotinic Occludes “rewarding” effects Smoking cessation Toxicity: Nausea and vomiting, seizures,
acetylcholine receptor of the of smoking • heightened psychiatric changes
α4β2-type awareness of colors

• Cytisine: Natural analog (extracted from laburnum flowers) of varenicline

(continued)
 CHAPTER 32 Drugs of Abuse 589

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Application Interactions
BENZODIAZEPINES
• Oxazepam, Positive modulators of the Enhances GABAergic Delirium tremens Half-life 4–15 h • pharmacokinetics not
others GABAA receptors, increase synaptic transmission; affected by decreased liver function
frequency of channel attenuates withdrawal
opening symptoms (tremor,
hallucinations, anxiety) in
alcoholics • prevents
withdrawal seizures

• Lorazepam: Alternate to oxazepam with similar properties

N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST

• Acamprosate Antagonist of NMDA May interfere with forms of Treatment of alcoholism • Allergic reactions, arrhythmia, and low
glutamate receptors synaptic plasticity that effective only in combination or high blood pressure, headaches,
depend on NMDA receptors with counseling insomnia, and impotence •
hallucinations, particularly in elderly
patients

CANNABINOID RECEPTOR INVERSE AGONIST

• Rimonabant CB1 receptor inverse agonist Decreases neurotransmitter Approved in Europe from Major depression, including increased
release at GABAergic and 2006 to 2008 to treat risk of suicide
glutamatergic synapses obesity, then withdrawn
because of major side effects
• smoking cessation has
never been approved, but
remains an off-label
indication

REFERENCES Pharmacology of Drugs of Abuse

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C ASE STUDY ANSWER

When found by his parents, the patient was having visual exogenous cannabis with endocannabinoids that fine-tune
hallucinations of colorful insects. Hallucinations are often synaptic transmission and plasticity. While probably not
caused by a cannabis overdose, especially when hashish is fulfilling the criteria for addiction at present, the patient is at
ingested. The slower kinetics of oral cannabis are more dif- risk as epidemiologic studies show that drug abuse typically
ficult to control compared to smoking marijuana. The poor begins in late adolescence. The fact that he is not yet using
learning performance may be due to the interference of other drugs is a positive sign.